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Mitochondrial dysfunction in sepsis: mechanisms and therapeutic perspectives

Critical Care volume 28, Article number: 292 (2024) Cite this article

Abstract

Sepsis is a severe medical condition characterized by a systemic inflammatory response, often culminating in multiple organ dysfunction and high mortality rates. In recent years, there has been a growing recognition of the pivotal role played by mitochondrial damage in driving the progression of sepsis. Various factors contribute to mitochondrial impairment during sepsis, encompassing mechanisms such as reactive nitrogen/oxygen species generation, mitophagy inhibition, mitochondrial dynamics change, and mitochondrial membrane permeabilization. Damaged mitochondria actively participate in shaping the inflammatory milieu by triggering key signaling pathways, including those mediated by Toll-like receptors, NOD-like receptors, and cyclic GMP-AMP synthase. Consequently, there has been a surge of interest in developing therapeutic strategies targeting mitochondria to mitigate septic pathogenesis. This review aims to delve into the intricate mechanisms underpinning mitochondrial dysfunction during sepsis and its significant impact on immune dysregulation. Moreover, we spotlight promising mitochondria-targeted interventions that have demonstrated therapeutic efficacy in preclinical sepsis models.

Introduction

To advance understanding of sepsis and septic shock, the task force convened by the European Society of Intensive Care Medicine and the Society of Critical Care Medicine introduced the "Sepsis-3" definition between 2014 and 2015 [1]. This update redefined sepsis as life-threatening organ dysfunction caused by a dysregulated inflammatory response to infection [1]. Sepsis contributes to 11 million deaths out of the 48.9 million reported cases, accounting for 19.7% of all global deaths in 2017 [2, 3]. The request for novel therapeutic targets in sepsis management assumes paramount importance.

Mitochondria are primary energy generators and participate in cellular processes, such as maintaining redox balance, buffering Ca2+, and initiating apoptosis [4]. A mitochondrion contains two membranes, the outer mitochondrial membrane (OMM) and the inner mitochondrial membrane (IMM), forming the matrix and intermembrane space (IMS) [5]. The mitochondrial respiratory chain comprises five complexes localized within the IMM: complex I, II, III, IV, and V. Complexes I–IV receive electrons, creating an electrochemical gradient of proton across the IMM referred to as mitochondrial membrane potential (ΔΨm). This ΔΨm is utilized by the complex V (F1F0 ATP synthase) to drive the production of ATP [6].

Accumulative evidence suggests that mitochondria play crucial roles in the pathogenesis of sepsis [7, 8]. Both laboratory studies and clinical investigations have documented the increase in mitochondrial damage during sepsis [9, 10]. Mitochondrial dysfunction occurs when mitochondria, fail to function properly upon damage. Mitochondria are not only involved in energy production, but also play critical roles in regulating cell metabolism and several cellular processes. The effects of mitochondrial dysfunction are enormous, including energy deficiency and activation of multiple pathways that alter cell function and fate. In the context of sepsis, the damaged mitochondria actively partake in shaping the inflammatory response via various signaling pathways [11]. Advances in mitochondria-targeted therapeutics have demonstrated that improving mitochondrial quality can reduce sepsis-induced inflammation, organ failure, and consequent mortality [12,13,14]. Thus, regulating mitochondrial quality is emerging as a promising strategy for sepsis treatment.

This review seeks to explore the complex mechanisms underlying mitochondrial dysfunction in sepsis and its profound influence on immune dysregulation. Additionally, we highlight promising interventions targeted at mitochondria that have shown therapeutic effectiveness in preclinical sepsis models. By comprehensively understanding the interplay between mitochondrial integrity and immune responses, we strive to pave the way for the development of novel and effective therapeutic approaches in combating sepsis-associated morbidity and mortality.

Mitochondrial stress and damage during sepsis

Sepsis triggers significant stress to mitochondria within immune cells and various tissues, leading to structural distortions, potential loss, and a marked decrease in respiratory activity. This section explores the specifics of the mitochondrial damage and the underlying mechanisms.

Mitochondrial damage

Despite the limited amount, clinical data clearly indicate mitochondrial dysfunction during sepsis. For instance, Japiassu and colleagues demonstrated that peripheral blood mononuclear cells (PBMCs) from septic shock patients have impaired mitochondrial ATP synthase activity [15]. Garrabou et al. observed inhibition of respiratory complexes in the PBMCs from septic patients without shock or multi-organ failure (MOF), suggesting that mitochondrial impairment precede these symptoms [16]. The platelets from septic patients showed lower activity of mitochondrial nicotinamide adenine dinucleotide dehydrogenase (NADH), complex I, I/III, and IV [17]. In addition to blood cells, muscle tissue of septic patients has also been reported with mitochondrial dysfunction and ATP depletion [18, 19]. Severe cardiac impairment has been observed in the non-surviving septic patients, with histologic analysis of heart sections showing mitochondrial cristae derangement (Table 1) [20].

Table 1 Mitochondrial damage during sepsis
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In animal models, cecal ligation and puncture (CLP), endotoxins/bacteria administration, and colon ascendens stent peritonitis (CASP) are commonly utilized to trigger sepsis [21]. Studies using these models support the clinical findings, highlighting the substantial impact of sepsis on mitochondrial homeostasis (Table 1). However, it is essential to acknowledge the presence of conflicting data showing unchanged or even increased mitochondrial activity in some cases, as previously discussed [22, 23]. Variables such as the nature of the septic insult, the severity of sepsis, timing of assessments, and methods of measurement may contribute to the discrepancies [24,25,26].

In addition, the common practice of using isolated cells or mitochondria from septic tissues for complex activity assays may not accurately reflect the in vivo mitochondrial status. This issue arises from the absence of circulating substances, such as cytokines, in vitro, which play pivotal roles in regulating mitochondrial respiration [16]. For instance, Boulos et al. demonstrated that serum from septic patients significantly reduced endothelial cell mitochondrial respiration compared to serum from healthy individuals, revealing the impact of circulating substances on mitochondrial function during sepsis [27].

Furthermore, normalization methods profoundly influence the evaluation of mitochondrial function. In a previous study, Fredriksson et al. measured the complex I activities in intercostal muscle mitochondria from septic patients and observed a 60% decrease when normalized to the dry weight of the muscle. However, no difference was found when normalization was conducted against citrate synthase activity. This was because the citrate synthase activity also declined during sepsis [28], emphasizing the importance of meticulous methodological consideration in such analyses.

Mechanisms of mitochondrial damage

Mitochondrial injury during sepsis is regulated by several factors, including reactive nitrogen species (RNS)/reactive oxygen species (ROS), mitophagy, mitochondrial dynamics, and mitochondrial membrane permeabilization, etc. In this section, we will examine the regulatory roles of these factors in mitochondrial health amidst septic conditions.

RNS/ROS burst

One of the well-exploited triggers of mitochondrial damage is nitric oxide (⋅NO), an RNS that is produced by inducible nitric oxide synthase (iNOS) [40]. ⋅NO could be converted to other reactive nitrogen species such as nitrite (NO2−) and nitrogen dioxide (·NO2) (Fig. 1) [41]. Escames et al. have investigated the role of iNOS in skeletal muscle mitochondria using a CLP mouse model. They observed a reduction in mitochondrial respiratory complex activity accompanied by elevated expression of iNOS during sepsis. In contrast, the iNOS-deficient mice did not exhibit such mitochondrial impairment [40]. A similar observation has been observed in the liver mitochondria of LPS-treated mice [42]. In line with these, inhibition of mitochondrial respiration induced by septic serum could be mitigated by the nitric oxide synthase inhibitor [27]. These data collectively suggest that iNOS play a crucial role in mitochondrial damage during sepsis.

Fig. 1
figure 1

Pathways of RNS and ROS production in sepsis. Excessive nitric oxide is generated by both cytosolic and mitochondrial iNOS during sepsis. The nitric oxide can be converted to other reactive nitrogen species (RNS), such as nitrite and nitrogen dioxide. On the other hand, excessive reactive oxygen species (ROS) are produced by NOXs and mitochondrial electron transport chain (ETC). Nitric oxide and superoxide react to form additional derivatives, notably the highly toxic peroxynitrite. The accumulation of these reactive species inflicts damage to cellular components, including lipids, proteins, and nucleic acids, thereby compromising mitochondrial respiration and integrity

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Sepsis also stimulates the formation of ROS. Superoxide radical (O2·−) originates from nicotinamide adenine dinucleotide phosphate oxidases (NOXs) and mitochondria ETC [43]. O2·− is considered unstable and can be converted to other types of ROS (Fig. 1) [44]. On the other hand, declines in the antioxidative system happen during sepsis. For example, sirtuin proteins, which can protect cells from oxidative stress, have been found to decrease after septic insults [45, 46]. Oxidative stress occurs when ROS level overwhelms the antioxidant defense system in cells, causing damage to lipids, proteins, and nucleic acids [47].

Mechanistically, ·NO selectively binds to complex IV, where it competes with O2 for the binuclear CuB/cytochrome a3 center, resulting in a reversible inhibition of the complex IV [48]. While ·NO is relatively unreactive, its reaction with ROS gives rise to a series of more reactive derivatives [49]. Peroxynitrite (ONOO–) is one of the highly toxic derivatives (Fig. 1). Peroxynitrite can cause impairments to mitochondria via oxidation, irreversibly inhibiting mitochondrial complex I, CII, CIV, ATP synthase, and several critical enzymes. Consequently, the RNS/ROS exert a profound inhibitory effect on mitochondrial respiration and contribute to mitochondrial damage during sepsis [50].

Mitophagy

Mitophagy is a specialized form of autophagy that selectively degrades damaged mitochondria (Fig. 2a) [51]. Impaired mitophagy prevents mitochondrial turnover, leading to the accumulation of dysfunctional mitochondria [52]. Growing evidence shows that inhibition of mitophagy occurs in immune cells during the inflammatory response. Yu et al. found that Caspase-1 in macrophages cleaves Parkin to inhibit mitophagy upon inflammasome activation [53]. Similarly, Patoli et al. demonstrated mitophagy inhibition in the LPS/IFN-γ-treated macrophage cells, CLP mouse model, and septic patients, revealing caspases 1/11 dependent PINK1 degradation in the early stage of inflammation [54]. Additionally, inflammation-induced pro-IL-1α can interact with cardiolipin, preventing it from serving as a mitophagy receptor [55]. AMP-activated protein kinase (AMPK) is a regulator of autophagy, which positively regulates mitochondrial clearance by activating unc-51 like autophagy activating kinase 1 (ULK1) [56]. TLR4 signaling has been reported to prevent the activation of AMPK in neutrophil and macrophage [57]. Thus, lack of AMPK activation could be another reason for the accumulation of damaged mitochondria in sepsis.

Fig. 2
figure 2

Pathways of mitophagy and mitochondrial dynamics. a The most extensively studied mitophagy pathway involves PTEN-induced kinase 1 (PINK1) and E3 ubiquitin ligase Parkin. Upon ΔΨm loss, PINK1 is stabilized on the OMM, where it recruits and activates Parkin. Parkin subsequently ubiquitinates mitochondrial surface proteins, signaling the autophagosome to encapsulate the dysfunctional mitochondrion. Adaptor proteins including p62, Optineurin (OPTN), calcium binding and coiled-coil domain-containing protein 2 (NDP52), tax1-binding protein 1 (TAX1BP1), and next to BRCA1 gene 1 protein (NBR1) play a role in linking the ubiquitin chains to microtubule-associated protein 1 light chain 3 (LC3) on phagophores. On the other hand, some mitochondrial receptor proteins (or lipids) such as FUN14 domain containing 1 (FUNDC1), prohibitin (PHB), BCL2 interacting protein3 (BNIP3), Nip3-like protein X (NIX), cardiolipin, and syntaxin 17 (STX17) can recruit phagophore membranes independent of ubiquitin. The autophagosome finally fuses with a lysosome for the degradation and recycling of mitochondria. b Mitochondrial dynamics is regulated by several dynamin-related GTPases, including Mfn1/2, OPA1, Drp1, Fis1, MiD49/51, and Mff. Mfn1/2 facilitate the fusion of the OMM, while OPA1 is responsible for the fusion of the IMM. The fission process is initiated by the endoplasmic reticulum (ER)-mediated pre-constriction of mitochondria. Drp1 is recruited to the pre-constricted sites by receptors (Mff, Fis1, and MiD49/51). After binding to OMM, Drp1 oligomerizes into ring-shaped filaments. Hydrolysis of GTP by Drp1 results in constriction and closure of the ring. Dnm2 is finally recruited to the constricting site to complete the fission. In addition to the ER, lysosome and Golgi-derived vesicles have also been reported to regulate mitochondrial fission

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Interestingly, activation of mitophagy also occurs during immune response. Ip and colleagues showed that interleukin 10 (IL-10) promotes mitophagy by inhibiting the mammalian target of rapamycin (mTOR) in macrophages [58]. Moreover, nuclear factor κB (NF-κB) facilitates mitophagy by inducing the expression of autophagic receptor p62. This NF-κB-p62-mitophagy pathway exists as a self-limiting mechanism to prevent excessive inflammation and maintain homeostasis [59]. Sestrin 2 (SESN2) also play a role in the p62-dependent mitophagy [60]. Extended LPS stimulation upregulates the protein level of SESN2, which interacts with p62 to facilitate its aggregation on mitochondria. Besides, SESN2 activates the autophagic machinery by raising the ULK1 protein level [60]. Overall, the accumulation of damaged mitochondria is likely to result from both forward and reverse regulation of mitophagy. How these different mitophagic pathways are spatiotemporally coordinated in sepsis is still elusive. Given the critical role of damaged mitochondria in promoting immune response (which will be discussed in the later section), it is plausible that early-stage inhibition of mitophagy promotes the accumulation of dysfunctional mitochondria and benefit bacterial defense [54], while late-stage activation of mitophagy represents a cellular attempt to mitigate inflammation and restore host homeostasis [59].

Unlike in immune cells, the overall mitophagy in various organs is enhanced during sepsis. The heart samples from LPS-challenged mice have shown decreased mitochondrial number and volume, suggesting autophagic removal of mitochondria [29, 61]. Immunoblot analysis of kidney tissue from LPS or CLP-treated mice has shown a decrease in mitochondrial protein levels (TOM20 and TIM23) compared with control mice, providing substantial evidence that mitophagy is induced during the sepsis-caused acute kidney injury [62]. It was also demonstrated that the mitophagy is mainly mediated by the PINK1/Parkin/OPTN pathway [62]. Reductions of mitochondrial mass were also reported in the liver of CLP or LPS-treated septic mice [63]. These studies collectively suggest that mitophagy is enhanced in various organs during sepsis.

Mitochondrial dynamics

Mitochondria constantly undergo fusion and fission processes (Fig. 2b). Fusion forms interconnected mitochondrial networks, promoting content exchange, which is essential for the integrity of the mitochondrial genome and proteome. Conversely, fission fragments mitochondria, aiding in the elimination of dysfunctional parts [64, 65]. Dysregulation of mitochondrial dynamics is a crucial mechanism that induces mitochondrial stress [66].

During sepsis, excessive mitochondrial fragmentation happens in various tissues, revealing the change in mitochondrial dynamics [62, 67, 68]. To exploit the influence of mitochondrial fission in sepsis, Gonzalez et al. treated rats with the Drp1 inhibitor mdivi-1 before CLP administration. This treatment restored mitochondrial shape and prevented the reduction of complex activities and apoptosis in hepatocytes [68]. Similar beneficial effects of mdivi-1 have been confirmed in other studies [13, 69, 70]. Pharmacological administration of alternative fission inhibitors, such as P110 (inhibit Drp1/Fis1 interaction), also showed protection to mitochondria under septic stress [71, 72]. These findings demonstrate that excessive fission significantly contributes to the impairment of mitochondria during sepsis. Inhibition of this process, therefore, is an effective method to restore mitochondrial function.

Mitochondrial membrane permeabilization

Mitochondrial membrane pores cause mitochondrial swelling, content loss, and ΔΨm dissipation [73]. Three principal mechanisms involved in pore formation during sepsis are mitochondrial outer membrane permeabilization (MOMP), mitochondrial permeability transition (MPT), and more recently characterized gasdermins (GSDMs)-mediated mitochondrial membrane opening (Fig. 3).

Fig. 3
figure 3

Mechanisms of mitochondrial membrane permeabilization in sepsis. Three principal mechanisms are implicated in sepsis-related mitochondrial membrane pore formation. Mitochondrial outer membrane permeabilization (MOMP) is mediated by Bcl-2 family proteins Bax/Bak and regulated tBid. Large BAK/BAX pores allow the protrusion of IMM into the cytosol, therefore, enabling the escape of mitochondrial matrix contents. Mitochondrial permeability transition pore (MPTP) represents another type of mitochondrial pore in sepsis. Despite the opening mechanism of MPTP is still elusive, mitochondrial components such as F1FO (F)-ATP synthase, ANT, and Cyp-D have been confirmed to play pivotal roles in this process. Gasdermins (GSDMs) are well-known to form pores on plasma membrane during immune response. Recent advances have demonstrated that GSDMs target both the inner and outer mitochondrial membranes via their strong binding preference to cardiolipin. ROS promote the externalization of cardiolipin from IMM to OMM, thus, positively regulate GSDMs-mediate pore formation. Overall, mitochondrial membrane permeabilization leads to mitochondrial swelling, content loss, and dissipation of membrane potential during sepsis

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MOMP is mediated by Bcl-2 family proteins Bax and Bak, which open the OMM in response to apoptotic signals. MOMP leads to mitochondrial damage and release of intermembrane space molecules like cytochrome C [74]. Large Bax/Bak pores also allow the IMM to protrude out of mitochondria, releasing matrix contents [75, 76]. Cytokines such as INF-γ and TNF-α could be recognized by the cell membrane death receptors, thereby activating caspase-8 during sepsis [77]. The activated caspase-8 cleaves Bid, generating a truncated form of Bid (tBid), which translocates to mitochondria and activates Bax/Bak to induce MOMP and cell death [78,79,80]. Chuang et al. have observed increased tBid in mitochondrial fractions of various tissues from the CLP-treated mouse, while Bid deficiency significantly reduced the downstream cell death [81]. In addition to caspase-8, caspase-1 has also been reported to cleave Bid and induce MOMP during the inflammatory response of macrophage [82].

The occurrence of MPT has been described in several septic models [83,84,85,86]. Pharmacological inhibition of MPT by cyclosporin A (CsA) can significantly attenuate mtDNA release and mitochondrial dysfunction in these models, suggesting MPT’s crucial role in sepsis-induced mitochondrial damage [83,84,85]. Although the exact molecular composition and mechanism of MPT remains a topic of ongoing research, key components are believed to include the F1FO (F)-ATP synthase, adenine nucleotide translocator (ANT), cyclophilin D (Cyp-D), and voltage-dependent anion channel (VDAC) [87]. These components assemble into a supramolecular pore (MPTP) at the interface of the IMM and OMM [88]. Elevated ROS levels can induce MPTP opening through oxidative modifications of MPT constituents or other mitochondrial proteins [89, 90].

GSDMs are key players in immune response, particularly in mediating pyroptosis. During inflammation, GSDMs are cleaved by caspases to release their active N-terminal fragments (GSDMs-N). GSDMs-N translocate to the plasma membrane, forming pores and disrupting the membrane [91]. Recent findings indicate that GSDMs also target mitochondrial membranes, representing a new pathway of mitochondrial permeabilization [92,93,94,95,96,97]. Time-lapse imaging analysis revealed that mitochondrial damage occurs much earlier than the opening of cell membrane, suggesting that GSDMs-N permeabilizes the mitochondria before cell membrane [92, 93]. This phenomenon has been attributed to the strong binding preference of GSDMs-N to mitochondrial cardiolipin [92]. Of note, ROS promote the externalization of cardiolipin from IMM to OMM, explaining the accumulation of GSDMD-N on OMM, as cardiolipin predominantly localizes in the IMM under normal conditions [95]. Overall, GSDM-mediated pore formation represents a novel pathway of mitochondrial permeabilization during immune response.

Damaged mitochondria are potent triggers of immune response and metabolic reprogramming

The innate immune response plays a key role in the pathophysiology of sepsis. Upon activation, pattern recognition receptors (PRRs) initiate signaling cascades, leading to the nuclear translocation of NF-κB, interferon regulatory factor (IRF), and other transcription factors. These transcription factors initiate the production of pro-inflammatory cytokines, chemokines, type I interferons (IFNs), etc. [98]. In the past few decades, damaged mitochondria have been widely demonstrated as a crucial regulator of innate immunity, particularly through the NLRP3, TLR9, and cGAS pathways. Thus, mitochondria damage is not simply a passive outcome under stress conditions, but actively contributes to the inflammatory response that is essential for the defense of pathogens. However, in the context of sepsis, excessive or persistent inflammation can cause a fatal inflammatory imbalance in the body, which ultimately leads to tissue and organ damage [99]. In this section, we will highlight the roles of mitochondria in regulating inflammatory pathways.

NLRP3 inflammasome pathway

NLRP3 inflammasome activation

The NLRP3 inflammasome activates pro-caspase-1, which cleaves pro-inflammatory cytokines such as interleukin-1β (IL-1β) and interleukin-18 (IL-18) to promote their maturation [100]. Current studies, mainly in monocytes/macrophages, have revealed several regulatory roles of mitochondria in NLRP3 inflammasome activation. Mitochondrial ROS (mtROS) have been demonstrated as essential molecules for NLRP3 inflammasome activation. In sepsis models, inhibition of mtROS reduces the NLRP3 inflammasome-mediated cytokine production [101,102,103]. Several studies have provided insights into the mechanisms by which ROS modulate NLRP3 activation. In 2010, Zhou et al. identified thioredoxin (TRX)-interacting protein (TXNIP) as a binding partner of NLRP3. Under basal conditions, TXNIP binds to TRX, being unavailable to NLRP3. ROS promote NLRP3 activation by triggering the dissociation of TXNIP from TRX [104]. In another study, mtROS were confirmed to facilitate NLRP3 inflammasome activation through promoting its deubiquitination [105]. Interestingly, Bauernfeind and colleagues reported that ROS increase the NLRP3 expression instead of activating it, suggesting a translational regulation of NLRP3 by ROS [106].

mtDNA also regulates NLRP3 inflammasome activation. Nakahira et al. demonstrated that preventing MPT-mediated mtDNA release significantly reduces IL-1β secretion in macrophages after LPS + ATP challenge [83]. Interestingly, NLRP3 inflammasome is preferentially activated by oxidized mtDNA (ox-mtDNA), rather than normal mtDNA [107]. Zhong et al. found that TLR4 signalling promotes de novo mtDNA synthesis to sustain the generation of ox-mtDNA, since the newly synthesized mtDNA is not packaged and is highly susceptible to oxidation [108]. Before being released into cytosol, the ox-mtDNA undergoes a cleavage process to become 500–650 bp fragments. Xian et al. recently identified the flap structure-specific endonuclease 1 (FEN1) as the key mediator of this process [109]. AIM2 inflammasome can also be activated by the mtDNA. Unlike NLPR3 inflammasome, AIM2 inflammasome is activated by normal DNA to ox-mtDNA [107, 108].

Spatial association between mitochondria and NLRP3

The spatial association of NLRP3 inflammasome with organelles is critical for its activation. Early studies posited mitochondria or mitochondria-associated membrane (MAM) as the docking sites of NLRP3, while more recent publications have implicated trans-Golgi network (TGN) and microtubule-organizing center (MTOC) [110,111,112,113,114].

Zhou et al. reported that inflammatory stimuli trigger NLRP3 to co-localize with mitochondria and MAM in 2010 [112]. This spatial vicinity may facilitate the sensing of mitochondria-derived inflammatory signals [112, 115]. Microtubules also play a role in the mitochondria-NLRP3 association. Mechanistically, mitochondrial dysfunction during inflammation reduces NAD+ (oxidized form of nicotinamide adenine dinucleotide) generation, which in turn inhibits NAD+-dependent α-tubulin deacetylase sirtuin 2, leading to an increase in α-tubulin acetylation. The acetylated α-tubulin subsequently promoted dynein-dependent transport of mitochondria to NLRP3 [116]. Inflammatory stimuli also trigger the transport of NLRP3 towards mitochondria, which is orchestrated by microtubule-affinity regulating kinase 4 (MARK4). Depletion of MARK4 impairs NLRP3 spatial arrangement and inflammasome activation [111].

Mitochondrial antiviral-signaling protein (MAVS) and cardiolipin mediate the anchorage of NLRP3 on mitochondria [117,118,119,120,121]. MAVS lacking mitochondrial targeting domain cannot recruit NLRP3 or induce NLRP3 oligomerization, suggesting its mitochondrial localization is essential for NLRP3 inflammasome activation [120]. Given the well-established role of MAVS in recognizing virus RNA, it is plausible that microbial RNA plays a role in promoting the MAVS-dependent recruitment of NLRP3 during bacterial infection [121, 122]. In line with this, virus or Escherichia coli-induced activation of NLRP3 inflammasome was confirmed to greatly depend on MAVS [121], whereas LPS + ATP or LPS + nigericin (without microbial RNA) induced NLRP3 inflammasome activation is only partially affected by MAVS [117, 120, 121]. Cardiolipin also interacts with NLRP3 and contributes to the inflammasome activation [118]. A recent study suggested that cardiolipin recruits both NLRP3 and caspase-1, serving as a platform for inflammasome assembly [119].

Several recent publications have highlighted the involvement of Golgi apparatus and MTOC in NLRP3 inflammasome activation [113, 114, 123]. It is likely that NLRP3 protein is first transported to meet mitochondria along the microtubules, after which NLRP3 redistributes to the adjacent Golgi apparatus [115, 124]. Then, the NLRP3 is transported to the MTOC and reorganized into a single speck structure. At the MTOC, NLRP3 engages with NEK7, a centrosome-localized kinase that is essential for NLRP3 inflammasome activation (Fig. 4) [111, 114, 123, 125, 126].

Fig. 4
figure 4

Mitochondria-regulated inflammatory pathways in sepsis. Pattern recognition receptors (PRRs) of immune cells recognize pathogen-associated molecular patterns (PAMPs) from microbes or damage-associated molecular patterns (DAMPs) released by damaged host cells. a Mitochondria orchestrate the activation of the NLRP3 inflammasome. mtROS and ox-mtDNA promote the NLRP3 inflammasome activation after their release from the damaged mitochondria. Additionally, mitochondrial antiviral-signaling protein (MAVS) and cardiolipin mediate the spatial association between mitochondria and NLRP3, which may facilitate a rapid and efficient sensing of the inflammatory signals from the damaged mitochondria by NLRP3. Early studies posited mitochondria or mitochondria-associated membrane (MAM) as the docking sites of NLRP3, while more recent publications have indicated the involvement of Golgi and microtubule-organizing center (MTOC). It could be plausible that NLRP3 proteins are first transported to meet mitochondria, after which NLRP3 redistributes to the adjacent Golgi apparatus as oligomeric cages. Then, the NLRP3 cages are transported to MTOC and reorganized into a single inflammasome speck. Activated NLRP3 inflammasome mediates the activation of pro-caspase-1, which proteolytically processes GSDMs and pro-inflammatory cytokines. The matured cytokines are released from the GSDMs pores to transmit inflammatory signals. b Mitochondria regulate the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway. cGAS is activated upon mtDNA binding, leading to the synthesis of cyclic GMP-AMP (cGAMP). cGAMP then induces a conformational change in STING, leading to its activation at ER. Activated STING translocates to Golgi, where it activates transcription factors interferon regulatory factor 3 (IRF3) and nuclear factor κB (NF-κB) to initiate the production of type I interferons and other pro-inflammatory cytokines that are required for effective immune response against pathogens. c Mitochondria regulate the TLR9 pathway. mtDNA shares similarities with bacterial DNA, thus can be recognized by TLR9. As with other TLRs and cGAS-STING axis, TLR9 pathway activates IRF3 and NF-κB to regulate the inflammatory response

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cGAS-STING pathway activation

The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is another mitochondria-regulated inflammatory pathway. cGAS detects cytosolic double-stranded DNA and initiates an innate immune response [127] (Fig. 4). Both normal and oxidized mtDNA can be recognized by cGAS [128], but ox-mtDNA is more resistant to degradation by the cytosolic nuclease 3' repair exonuclease 1, increasing its likelihood of interaction with cGAS [129].

In the CLP mouse model, Huang et al. have demonstrated that mtDNA can be released via the GSDMD pore to activate cGAS-STING pathway [94]. This pathway not only enhances the inflammatory response but also suppresses lung endothelial cell proliferation, which compromises the recovery capacity of host. Notably, the deletion of cGas gene provided mice with substantial protection from lung injury 72 h post-CLP, suggesting that cGAS-STING pathway is crucial in septic lung inflammation [94].

Studies have shown that circulating cell-free mtDNA levels are elevated in septic patients and animal models, correlating with poor prognosis [130,131,132,133]. Like cytosolic mtDNA, circulating mtDNA activates the cGAS-STING pathway and promotes inflammation during sepsis [133]. In CLP mice, the mtDNA-cGAS-STING signal promotes intestinal inflammation and gut barrier dysfunction, which could be significantly attenuated by removing circulating mtDNA with DNase I [134]. Mechanistically, host nuclear DNA, mtDNA and bacterial DNA can be recognized by cGAS, while to what extent mtDNA contributes to the cGAS-STING pathway activation awaits investigation [135, 136].

TLR9 pathway activation

TLR9 is initially known for sensing unmethylated CpG DNA motifs (consisting of a central cytosine-guanine dinucleotide plus flanking regions) from bacterial and viral DNA during innate immune response [137, 138]. However, a subsequent study suggests that TLR9 also recognizes endogenous mtDNA, which shares similarities with bacterial DNA [139]. This interaction stands for another inflammatory pathway regulated by mitochondria in sepsis (Fig. 4).

Experimental models have shown that intravenous administration of mitochondrial debris can elicit an immune response comparable to that of CLP treatment. However, Tlr9 knockout (KO) or DNase pretreatment of the mitochondrial debris greatly attenuates the inflammatory response, suggesting the crucial role of the mtDNA-TLR9 axis in sepsis [140]. In line with this, TLR9 inhibitor OND-I suppresses caspase 1 activation and IL–1β production in LPS-challenged cardiomyocytes [38]. Moreover, Tlr9 KO reduced renal dysfunction and splenic apoptosis after CLP treatment, and increased survival at 96 h [141]. Interestingly, Plitas and colleagues found that Tlr9 KO mice exhibited better bacterial clearance and greater survival than wide type (WT) mice after CLP treatment. The protective effects were associated with increased recruitment of granulocytes to the peritoneum by dendritic cells (DCs) [142]. These findings suggest that TLR9 might have a major role in the immunopathogenesis of polymicrobial sepsis compared to other TLRs [142].

Metabolic reprogramming

During sepsis, a widespread alteration in the metabolic pattern occurs in virtually all cell types, leading to a shift from oxidative phosphorylation (OXPHOS) to glycolysis—a phenomenon known as “metabolic reprogramming” [143]. The metabolic reprogramming is driven by the downregulation of OXPHOS due to mitochondrial dysfunction and the upregulation of glycolysis through the enhancement of glycolytic pathways [144]. This shift in metabolism profoundly affects immune response and organ function in sepsis.

In the immune context, glycolysis, albeit less efficient than OXPHOS, allows rapid generation of ATP and synthesis of metabolic intermediates necessary for immune cell activation and proliferation [145]. Glycolytic inhibitors, such as 2-deoxyglucose (2-DG), have been shown to reduce systemic inflammation in sepsis, indicating their potential in therapeutic interventions [146, 147]. The metabolic reprogramming is also implicated in the development MOF. An early histopathologic study of patients dying of sepsis has revealed that the actual cell death in most organs is minimal, despite severe clinical signs of MOF [148]. This observation indicates that the organ failure is functional rather than structural [149]. Given that mitochondrial dysfunction results in less efficient ATP production, cells in affected organs face an energy crisis during sepsis. Consequently, metabolic reprogramming and the resultant bioenergetic failure are recognized as critical contributors to MOF in sepsis [150]. A key question regarding MOF in sepsis is whether it represents an adaptive or maladaptive event. Singer et al. have suggested that sepsis-induced MOF might be an adaptation by the host to increase the chances of cell survival against the infection. This response mirrors a state of “hibernation” in which non-essential functions are downregulated [9, 149].

Mitochondria-based therapeutic interventions

Effective treatments are crucial for aiding critically ill patients with sepsis. Previous research has shown that sepsis survivors responded early to the illness with induction of mitochondrial biogenesis and antioxidant defense, indicating the potential of maintaining mitochondrial homeostasis for sepsis therapy [19].

Antioxidants

Given the roles of ROS in triggering mitochondrial damage and inflammation, antioxidants have been extensively studied as therapeutic agents against sepsis. Mitochondria-targeted antioxidants have shown better effects on reducing inflammation compared to the untargeted equivalents [101, 151, 152]. The most frequently used mitochondria-specific antioxidants include MitoQ, MitoVitE, and MitoTempol (Fig. 5) [153].

Fig. 5
figure 5

Mitochondria-based therapeutic interventions. Mitochondria-targeted antioxidants such as MitoQ, MitoVitE, and MitoTempol are selectively targeted to mitochondria by conjugating to a lipophilic cation decyl-triphenylphosphonium (TPP+). The positive charge of cation enables the molecules to accumulate in mitochondrial matrix, therefore, specifically quench the mitochondrial ROS. Non-antioxidants Urolithin A, Mdivi-1, and Cyclosporin A improve mitochondrial quality by promoting mitophagy, inhibiting mitochondrial fission, and blocking MPTP, respectively. Metformin plays multiple roles on mitochondria, including enhancing mitophagy, reducing mtROS, preventing ox-mtDNA production, and inhibiting mitochondrial protein translation. These compounds target different aspects of mitochondria and exhibit great potential in reducing sepsis-induced mitochondrial damage, excessive inflammation, and organ dysfunction

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MitoQ

MitoQ is synthesized by conjugating ubiquinone with the lipophilic cation decyl-triphenylphosphonium (TPP+). Although it has not received approval from the U.S. Food and Drug Administration (FDA), MitoQ has been the subject of several clinical trials aiming to explore its potential benefits for treating oxidative pathologies [154]. Lowes et al. demonstrated that MitoQ protects mitochondria during sepsis, and suppresses pro-inflammatory cytokine release, leading to reduced acute liver and renal dysfunction [102]. The beneficial effects have also been confirmed in other organs, including the lung, intestinal barrier, skeletal muscle, and heart, leading to the increased survival rate of septic animals [12, 155,156,157]. Notably, MitoQ treatment 6 h after sepsis induction yielded comparable outcomes in comparison with immediate treatment in the diaphragm muscle. This property makes MitoQ a good candidate for clinical application, considering the typical delay between sepsis onset and treatment initiation [157].

MitoVitE

MitoVitE is a modified form of vitamin E, attached to the TPP+ [158]. Zang et al. examined its effects on cardiac dysfunction in a rat pneumonia-related sepsis model, and confirmed that a single dose of MitoVitE protected cardiac mitochondria, suppressed cytokine burst, and neutrophil infiltration in the myocardium, ultimately improving the cardiac function [101]. Another study using LPS/peptidoglycan (PepG)-induced sepsis rat model revealed that MitoVitE offers similar protection as MitoQ in improving mitochondrial health, mitigating inflammation, and reducing organ dysfunction [159].

MitoTempol

MitoTempol, constructed by combining the piperidine nitroxide (Tempol) with TPP+, is another mitochondria-targeted antioxidant [160]. In a rat model of fecal peritonitis, MitoTempol administration reduced IL-1β level, renal oxidative stress, and improved renal function [161]. Interestingly, while this study showed no beneficial effect on the core body temperature and survival rate [161], another investigation revealed that even a 6 h delayed MitoTempol therapy significantly improved core body temperature and increased the survival rate from 40 to 83% in CLP mice [35]. These contradictory results may be related to MitoTempol dosage. Insufficient dosing may fail to provide benefits, whereas excessive dosing may lead to over-accumulation of this cationic agent, resulting in mitochondrial damage [35]. Thus, fine-tuning the dosage is essential to minimize side effects and maximize therapeutic benefits.

NAD+

NAD+ is known for its functions in redox metabolism, immune response, aging, and DNA repair [162]. NAD+ shortage occurs during sepsis, prompting the exploration of NAD+ supplementation as a potential therapeutic strategy [163, 164]. NAD+ precursors, such as nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR), are emerging as novel candidates for sepsis treatment. These precursors, naturally present in food and widely used as health supplements, have shown potential in preclinical studies by mitigating mitochondrial dysfunction, oxidative stress, inflammatory response, and multiorgan injury associated with sepsis [164,165,166]. The precise regulatory mechanisms of NAD+ in sepsis remain incompletely understood. As a critical co-enzyme, NAD+ plays a role in alleviating oxidative stress, in part through the activation of sirtuins, like Sirt3, a mitochondria-localized sirtuin [164, 165].

Non-antioxidants

Several non-antioxidant agents targeting mitophagy, mitochondrial dynamics, mitochondrial permeabilization, and other pathways have been reported to mitigate sepsis (Fig. 5).

Urolithin A

Urolithin A (UA) is a natural anti-aging compound known for inducing mitophagy [167]. It has attracted significant attention for the role in regulating inflammation [168, 169]. Two clinical trials in elderly individuals have shown that UA is safe, bioavailable, and well-tolerated [170, 171].

UA has been reported to sustain mitochondrial health in cardiomyocytes challenged with LPS in vitro [172]. In mice, UA administration alleviated the LPS-induced cardiac depression [173]. Interestingly, this protection was diminished upon FUNDC1 knockout, indicating UA activates mitophagy in a FUNDC1-dependent manner [173]. UA pre-administration was also found to alleviate pulmonary injury upon LPS challenge, and improve the survival rate [174]. Overall, while research on UA for sepsis treatment is still nascent, the existing evidence suggests significant therapeutic potential. Future research using more appropriate sepsis models would be recommended, as LPS treatment does not recapitulate the complex pathophysiological consequence of human sepsis [175, 176].

Mdivi-1

Mdivi-1 was first identified as an inhibitor of mitochondrial fission via chemical screening in 2008, [177]. Thereafter, numerous articles have been published on Mdivi-1, confirming its potency in inhibiting mitochondrial fission, improving mitochondrial health, and protecting cells from stress under various circumstances [178]. The wide application of Mdivi-1 promotes the development of novel therapeutic strategies for mitochondria-related diseases, including sepsis.

Mdivi-1 was shown to protect liver and brain function in the CLP mice model [179, 180]. Moreover, Zhu et al. showed that Mdivi-1 significantly restored the function of multiple organs in CLP-treated rats, and extended the average survival time from 8.83 h to 60.3 h. In this study, Mdivi-1 was administered 12 h after sepsis, which mirrors a clinically relevant scenario [13]. Other fission inhibitors, like P100 and irisin, have also been reported to mitigate organ injury and reduce mortality after sepsis [71, 72, 181].

Cyclosporin A

CsA is an FDA approved compound that has been utilized as an anti-inflammatory drug to treat ocular surface diseases [182]. Cyclosporin A has been widely used as an immunosuppressant to prevent immune responses against transplanted organs in clinic [183]. CsA potentially inhibits immune response via two pathways. First, CsA inhibits MPTP by interacting with Cyp-D, thus, reducing DAMPs release from mitochondria [184]. Second, CsA forms a complex with cyclophilin A to inhibit calcineurin. This inhibition thereafter impairs the nuclear translocation of nuclear factor of activated T cells (NFAT) and NFκB in immune cells, leading to reduced production of iNOS, inflammatory cytokines and prostaglandins [185].

Over the past two decades, CsA has been reported to attenuate mtDNA release and mitochondrial damage in various septic models [83,84,85, 186]. These studies confirmed the protective effects of CsA on sepsis-induced organ dysfunction and mortality [83,84,85, 186]. CsA and NIM811 (a cyclophilin non-binding derivate of CsA that inhibits MPTP) rather than tacrolimus (a potent immunosuppressive compound which does not inhibit MPTP) provided protection against septic insult, suggesting that the beneficial effects of CsA were predominantly related to the inhibition of MPTP [84, 187]. However, Joshi et al. reported that tacrolimus provided similar cardiac protection as CsA upon LPS treatment [188]. This discrepancy maybe due to the severity of mitochondrial injury; CsA's MPTP inhibitory function becomes critical only when mitochondrial damage is severe.

Metformin

Metformin has been widely used to treat type 2 diabetes, whose clinical experience and trial data have raised almost no safety concerns [189, 190]. Several studies have highlighted the capacity of metformin in combating sepsis. For instance, Liu et al. demonstrated that metformin prevents excessive inflammation and the development of immunosuppression, increasing bacterial clearance in the lungs of septic mice [191]. Metformin also preserves brain, lung, liver, and colon barrier function by suppressing sepsis-induced inflammatory responses in animal models [192,193,194]. In human patients, several retrospective studies have been performed to evaluate the effect of metformin on sepsis. However, some of these studies revealed that metformin users (mainly diabetic patients) had lower in-hospital mortality than nonusers [195,196,197], while others showed that pre-admission of metformin did not change the mortality in septic patients [198, 199]. Two meta-analyses on these published cohort data were, therefore, performed to confirm the contribution of metformin in the mortality in septic adult patients. The results supported the positive effect of metformin in lowering the mortality of sepsis [200, 201]. Recently, three clinical trials (NCT05979038, NCT06181422, NCT05900284) evaluating the efficiency and safety of metformin in sepsis patients are ongoing, which will improve our understanding about the clinical feasibility of metformin in sepsis therapy.

The pharmacological mechanisms of metformin are multifaceted. Metformin regulates inflammation through both AMPK-dependent and independent pathways [202]. Mechanistically, metformin activates AMPK and suppresses the nutrient sensor mechanistic target of rapamycin (mTOR) complex 1 (mTORC1), which promotes autophagy. Autophagic elimination of damaged mitochondria subsequently limits NLRP3 inflammasome activation [203, 204]. AMPK also phosphorylate the PGC-1α to promote mitochondrial biogenesis [205]; or regulate transcription factors to reduce ROS and cytokine production [206, 207]. The activation of AMPK by metformin appears to be dose-dependent: Low-dose metformin drives AMPK activation through the lysosomal pathway, while high-dose metformin takes effect by inhibiting the complex I of respiratory chain, resulting in ATP shortage [208]. Xian et al. have revealed that the metformin-triggered ATP shortage can prevent the production of ox-mtDNA, thus, reducing NLRP3 inflammasome activation [204]. Metformin also diminishes IL-6 secretion, likely via the suppression of JNK and p38 MAPK [204]. Very recently, Marlies Cortés and colleagues uncovered that metformin’s anti-inflammatory effects rely on the expression of ZEB1, which restricts amino acid uptake, thereby downregulating the mTORC1 signaling and mitochondrial protein translation, leading to the inhibition of both acute and chronic inflammation [209].

Conclusion

Sepsis is a significant medical challenge characterized by a systemic inflammatory response. During sepsis, factors such as RNS/ROS, impaired mitophagy, altered mitochondrial dynamics, and membrane permeabilization result in the accumulation of defective mitochondria in immune cells and tissues. These damaged mitochondria promote the immune response via key pathways governed by NLRP3, TLR9, and cGAS. Preclinical studies have identified several agents that target mitochondrial quality control to reduce mitochondrial damage. These agents effectively attenuate inflammation and mortality, offering a novel approach for sepsis treatment.

Availability of data and materials

No datasets were generated or analysed during the current study.

Abbreviations

AKI:

Acute kidney injury

ALI:

Acute lung injury

AMPK:

AMP-activated protein kinase

ANT:

Adenine nucleotide translocator

BNIP3:

BCL2 interacting protein3

CALCOCO2/NDP52:

Calcium binding and coiled-coil domain-containing protein 2

CASP:

Colon ascendens stent peritonitis

cGAS:

Cyclic GMP-AMP synthase

CLP:

Cecal ligation and puncture

CsA:

Cyclosporin A

Cyp-D:

Cyclophilin D

DAMPs:

Damage-associated molecular patterns

DCs:

Dendritic cells

Drp1:

Dynamin-related protein 1

ER:

Endoplasmic reticulum

ETC:

Electron transport chain

FDA:

U.S. food and drug administration

FEN1:

Flap structure-specific endonuclease 1

Fis1:

Fission 1

FUNDC1:

FUN14 domain containing 1

GSDMs:

Gasdermins

ICUs:

Intensive care units

IFNs:

Interferons

IL:

Interleukin

IMS:

Intermembrane space

IRF:

Interferon regulatory factor

KO:

Knockout

LC3:

Microtubule-associated protein 1 light chain 3

L-OPA1:

Long OPA1 isoforms

LPS:

Lipopolysaccharides

MAM:

Mitochondria-associated membrane

MARK4:

Microtubule-affinity regulating kinase 4

MAVS:

Mitochondrial antiviral-signaling protein

Mff:

Mitochondrial fusion factor

Mfn1/2:

Mitofusin 1/2

MOF:

Multi-organ failure

MOMP:

Mitochondrial outer membrane permeabilization

MPT:

Mitochondrial permeability transition

mtDNA:

Mitochondrial DNA

MTOC:

Microtubule-organizing center

mTOR:

Mammalian target of rapamycin

mtROS:

Mitochondrial ROS

NADH:

Nicotinamide adenine dinucleotide dehydrogenase

NBR1:

Next to BRCA1 gene 1 protein

NFAT:

Nuclear factor of activated T cells

NF-κB:

Nuclear factor κB

NIX:

Nip3-like protein X

NLRs:

NOD-like receptors

NOXs:

Nicotinamide adenine dinucleotide phosphate oxidases

OMM:

Outer mitochondrial membrane

OPA1:

Optic atrophy 1

OPTN:

Optineurin

ox-mtDNA:

Oxidized mitochondrial DNA

PAMPs:

Pathogen-associated molecular patterns

PBMCs:

Peripheral blood mononuclear cells

PepG:

Peptidoglycan

PGC-1 β:

Peroxisome-proliferator-activated receptor γ coactivator 1 β

PHB:

Prohibitin

PINK1:

PTEN-induced kinase 1

PRRs:

Pattern recognition receptors

RNS:

Reactive nitrogen species

SESN2:

Sestrin 2

S-OPA1:

Short OPA1 isoforms

STING:

Stimulator of interferon genes

STX17:

Syntaxin 17

TAX1BP1:

Tax1-binding protein 1

tBid:

Truncated form of Bid

TCA:

Tricarboxylic acid

Tempol:

Piperidine nitroxide

TFAM:

Mitochondrial transcription factor A

TGN:

Trans-Golgi network

TLRs:

Toll-like receptors

TPP+ :

Decyl-triphenylphosphonium

TRX:

Thioredoxin

TXNIP:

Thioredoxin-interacting protein

UA:

Urolithin A

UCPs:

Uncoupling proteins

ULK1:

Unc-51 like autophagy activating kinase 1

VDAC:

Voltage-dependent anion channel

WT:

Wide type

ΔΨm:

Mitochondrial membrane potential

References

  1. Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, Bellomo R, Bernard GR, Chiche JD, Coopersmith CM, et al. The third international consensus definitions for sepsis and septic shock (sepsis-3). JAMA. 2016;315(8):801–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Rudd KE, Johnson SC, Agesa KM, Shackelford KA, Tsoi D, Kievlan DR, Colombara DV, Ikuta KS, Kissoon N, Finfer S, et al. Global, regional, and national sepsis incidence and mortality, 1990–2017: analysis for the Global Burden of Disease Study. Lancet. 2020;395(10219):200–11.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Srzic I, Nesek Adam V, Tunjic Pejak D. Sepsis definition: what’s new in the treatment guidelines. Acta Clin Croat. 2022;61(Suppl 1):67–72.

    PubMed  PubMed Central  Google Scholar 

  4. Misrani A, Tabassum S, Yang L. Mitochondrial dysfunction and oxidative stress in Alzheimer’s disease. Front Aging Neurosci. 2021;13:617588.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Schenkel LC, Bakovic M. Formation and regulation of mitochondrial membranes. Int J Cell Biol. 2014;2014:709828.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Vercellino I, Sazanov LA. The assembly, regulation and function of the mitochondrial respiratory chain. Nat Rev Mol Cell Biol. 2022;23(2):141–61.

    Article  CAS  PubMed  Google Scholar 

  7. Kong C, Song W, Fu T. Systemic inflammatory response syndrome is triggered by mitochondrial damage (review). Mol Med Rep. 2022;25(4):1–8.

    Article  Google Scholar 

  8. Lira Chavez FM, Gartzke LP, van Beuningen FE, Wink SE, Henning RH, Krenning G, Bouma HR. Restoring the infected powerhouse: Mitochondrial quality control in sepsis. Redox Biol. 2023;68:102968.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Singer M. The role of mitochondrial dysfunction in sepsis-induced multi-organ failure. Virulence. 2014;5(1):66–72.

    Article  PubMed  Google Scholar 

  10. Zhang W, Jiang H, Wu G, Huang P, Wang H, An H, Liu S, Zhang W. The pathogenesis and potential therapeutic targets in sepsis. MedComm (2020). 2023;4(6):e418.

    CAS  PubMed  Google Scholar 

  11. Marchi S, Guilbaud E, Tait SWG, Yamazaki T, Galluzzi L. Mitochondrial control of inflammation. Nat Rev Immunol. 2023;23(3):159–73.

    Article  CAS  PubMed  Google Scholar 

  12. Li R, Ren T, Zeng J. Mitochondrial coenzyme Q protects sepsis-induced acute lung injury by activating PI3K/Akt/GSK-3beta/mTOR pathway in rats. Biomed Res Int. 2019;2019:5240898.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Zhu Y, Kuang L, Wu Y, Deng H, She H, Zhou Y, Zhang J, Liu L, Li T. Protective effects of inhibition of mitochondrial fission on organ function after sepsis. Front Pharmacol. 2021;12:712489.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Tzanavari T, Varela A, Theocharis S, Ninou E, Kapelouzou A, Cokkinos DV, Kontaridis MI, Karalis KP. Metformin protects against infection-induced myocardial dysfunction. Metabolism. 2016;65(10):1447–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Japiassu AM, Santiago AP, d’Avila JC, Garcia-Souza LF, Galina A, Castro Faria-Neto HC, Bozza FA, Oliveira MF. Bioenergetic failure of human peripheral blood monocytes in patients with septic shock is mediated by reduced F1Fo adenosine-5’-triphosphate synthase activity. Crit Care Med. 2011;39(5):1056–63.

    Article  CAS  PubMed  Google Scholar 

  16. Garrabou G, Moren C, Lopez S, Tobias E, Cardellach F, Miro O, Casademont J. The effects of sepsis on mitochondria. J Infect Dis. 2012;205(3):392–400.

    Article  CAS  PubMed  Google Scholar 

  17. Protti A, Fortunato F, Artoni A, Lecchi A, Motta G, Mistraletti G, Novembrino C, Comi GP, Gattinoni L. Platelet mitochondrial dysfunction in critically ill patients: comparison between sepsis and cardiogenic shock. Crit Care. 2015;19(1):39.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Fredriksson K, Rooyackers O. Mitochondrial function in sepsis: respiratory versus leg muscle. Crit Care Med. 2007;35(9 Suppl):S449-453.

    Article  PubMed  Google Scholar 

  19. Carre JE, Orban JC, Re L, Felsmann K, Iffert W, Bauer M, Suliman HB, Piantadosi CA, Mayhew TM, Breen P, et al. Survival in critical illness is associated with early activation of mitochondrial biogenesis. Am J Respir Crit Care Med. 2010;182(6):745–51.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Soriano FG, Nogueira AC, Caldini EG, Lins MH, Teixeira AC, Cappi SB, Lotufo PA, Bernik MM, Zsengeller Z, Chen M, et al. Potential role of poly(adenosine 5’-diphosphate-ribose) polymerase activation in the pathogenesis of myocardial contractile dysfunction associated with human septic shock. Crit Care Med. 2006;34(4):1073–9.

    Article  CAS  PubMed  Google Scholar 

  21. Kingsley SM, Bhat BV. Differential paradigms in animal models of sepsis. Curr Infect Dis Rep. 2016;18(9):26.

    Article  PubMed  Google Scholar 

  22. Singer M, Brealey D. Mitochondrial dysfunction in sepsis. Biochem Soc Symp. 1999;66:149–66.

    Article  CAS  PubMed  Google Scholar 

  23. Corrêa TD, Jakob SM, Takala J. Mitochondrial function in sepsis. Crit Care Horizons. 2015;1:31–41.

    Google Scholar 

  24. Brealey D, Karyampudi S, Jacques TS, Novelli M, Stidwill R, Taylor V, Smolenski RT, Singer M. Mitochondrial dysfunction in a long-term rodent model of sepsis and organ failure. Am J Physiol Regul Integr Comp Physiol. 2004;286(3):R491-497.

    Article  CAS  PubMed  Google Scholar 

  25. Gellerich FN, Trumbeckaite S, Hertel K, Zierz S, Müller-Werdan U, Werdan K, Redl H, Schlag G. Impaired energy metabolism in hearts of septic baboons: diminished activities of Complex I and Complex II of the mitochondrial respiratory chain. Shock (Augusta, GA). 1999;11(5):336–41.

    Article  CAS  PubMed  Google Scholar 

  26. Brealey D, Singer M. Mitochondrial dysfunction in sepsis. Curr Infect Dis Rep. 2003;5(5):365–71.

    Article  PubMed  Google Scholar 

  27. Boulos M, Astiz ME, Barua RS, Osman M. Impaired mitochondrial function induced by serum from septic shock patients is attenuated by inhibition of nitric oxide synthase and poly(ADP-ribose) synthase. Crit Care Med. 2003;31(2):353–8.

    Article  CAS  PubMed  Google Scholar 

  28. Fredriksson K, Hammarqvist F, Strigard K, Hultenby K, Ljungqvist O, Wernerman J, Rooyackers O. Derangements in mitochondrial metabolism in intercostal and leg muscle of critically ill patients with sepsis-induced multiple organ failure. Am J Physiol Endocrinol Metab. 2006;291(5):E1044-1050.

    Article  CAS  PubMed  Google Scholar 

  29. Li Y, Feng YF, Liu XT, Li YC, Zhu HM, Sun MR, Li P, Liu B, Yang H. Songorine promotes cardiac mitochondrial biogenesis via Nrf2 induction during sepsis. Redox Biol. 2021;38:101771.

    Article  CAS  PubMed  Google Scholar 

  30. Tran M, Tam D, Bardia A, Bhasin M, Rowe GC, Kher A, Zsengeller ZK, Akhavan-Sharif MR, Khankin EV, Saintgeniez M, et al. PGC-1alpha promotes recovery after acute kidney injury during systemic inflammation in mice. J Clin Invest. 2011;121(10):4003–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Choumar A, Tarhuni A, Letteron P, Reyl-Desmars F, Dauhoo N, Damasse J, Vadrot N, Nahon P, Moreau R, Pessayre D, et al. Lipopolysaccharide-induced mitochondrial DNA depletion. Antioxid Redox Signal. 2011;15(11):2837–54.

    Article  CAS  PubMed  Google Scholar 

  32. Hansen ME, Simmons KJ, Tippetts TS, Thatcher MO, Saito RR, Hubbard ST, Trumbull AM, Parker BA, Taylor OJ, Bikman BT. Lipopolysaccharide disrupts mitochondrial physiology in skeletal muscle via disparate effects on sphingolipid metabolism. Shock. 2015;44(6):585–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. d’Avila JC, Santiago AP, Amancio RT, Galina A, Oliveira MF, Bozza FA. Sepsis induces brain mitochondrial dysfunction. Crit Care Med. 2008;36(6):1925–32.

    Article  PubMed  Google Scholar 

  34. Kokkinaki D, Hoffman M, Kalliora C, Kyriazis ID, Maning J, Lucchese AM, Shanmughapriya S, Tomar D, Park JY, Wang H, et al. Chemically synthesized Secoisolariciresinol diglucoside (LGM2605) improves mitochondrial function in cardiac myocytes and alleviates septic cardiomyopathy. J Mol Cell Cardiol. 2019;127:232–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Patil NK, Parajuli N, MacMillan-Crow LA, Mayeux PR. Inactivation of renal mitochondrial respiratory complexes and manganese superoxide dismutase during sepsis: mitochondria-targeted antioxidant mitigates injury. Am J Physiol Renal Physiol. 2014;306(7):F734-743.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Vanasco V, Saez T, Magnani ND, Pereyra L, Marchini T, Corach A, Vaccaro MI, Corach D, Evelson P, Alvarez S. Cardiac mitochondrial biogenesis in endotoxemia is not accompanied by mitochondrial function recovery. Free Radic Biol Med. 2014;77:1–9.

    Article  CAS  PubMed  Google Scholar 

  37. Markley MA, Pierro A, Eaton S. Hepatocyte mitochondrial metabolism is inhibited in neonatal rat endotoxaemia: effects of glutamine. Clin Sci. 2002;102(3):337–44.

    Article  CAS  Google Scholar 

  38. Yao X, Carlson D, Sun Y, Ma L, Wolf SE, Minei JP, Zang QS. Mitochondrial ROS Induces Cardiac Inflammation via a Pathway through mtDNA Damage in a Pneumonia-Related Sepsis Model. PLoS ONE. 2015;10(10):e0139416.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Crouser ED, Julian MW, Blaho DV, Pfeiffer DR. Endotoxin-induced mitochondrial damage correlates with impaired respiratory activity. Crit Care Med. 2002;30(2):276–84.

    Article  CAS  PubMed  Google Scholar 

  40. Escames G, Lopez LC, Tapias V, Utrilla P, Reiter RJ, Hitos AB, Leon J, Rodriguez MI, Acuna-Castroviejo D. Melatonin counteracts inducible mitochondrial nitric oxide synthase-dependent mitochondrial dysfunction in skeletal muscle of septic mice. J Pineal Res. 2006;40(1):71–8.

    Article  CAS  PubMed  Google Scholar 

  41. Nathan C, Shiloh MU. Reactive oxygen and nitrogen intermediates in the relationship between mammalian hosts and microbial pathogens. Proc Natl Acad Sci USA. 2000;97(16):8841–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Garcia JA, Ortiz F, Miana J, Doerrier C, Fernandez-Ortiz M, Rusanova I, Escames G, Garcia JJ, Acuna-Castroviejo D. Contribution of inducible and neuronal nitric oxide synthases to mitochondrial damage and melatonin rescue in LPS-treated mice. J Physiol Biochem. 2017;73(2):235–44.

    Article  CAS  PubMed  Google Scholar 

  43. Lopes-Pires ME, Frade-Guanaes JO, Quinlan GJ. Clotting dysfunction in sepsis: a role for ROS and potential for therapeutic intervention. Antioxidants (Basel). 2021;11(1):88.

    Article  PubMed  Google Scholar 

  44. Lee YM, He W, Liou YC. The redox language in neurodegenerative diseases: oxidative post-translational modifications by hydrogen peroxide. Cell Death Dis. 2021;12(1):58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Zhao WY, Zhang L, Sui MX, Zhu YH, Zeng L. Protective effects of sirtuin 3 in a murine model of sepsis-induced acute kidney injury. Sci Rep. 2016;6:33201.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Labiner HE, Sas KM, Baur JA, Sims CA. Sirt3 deletion increases inflammation and mortality in polymicrobial sepsis. Surg Infect (Larchmt). 2023;24(9):788–96.

    Article  PubMed  Google Scholar 

  47. Sharma P, Jha AB, Dubey RS, Pessarakli M. Reactive oxygen species, oxidative damage, and antioxidative defense mechanism in plants under stressful conditions. J Bot. 2012;2012:217037.

    Google Scholar 

  48. Shiva S, Brookes PS, Patel RP, Anderson PG, Darley-Usmar VM. Nitric oxide partitioning into mitochondrial membranes and the control of respiration at cytochrome c oxidase. Proc Natl Acad Sci USA. 2001;98(13):7212–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Brown GC, Borutaite V. Inhibition of mitochondrial respiratory complex I by nitric oxide, peroxynitrite and S-nitrosothiols. Biochim Biophys Acta. 2004;1658(1–2):44–9.

    Article  CAS  PubMed  Google Scholar 

  50. Brown GC. Regulation of mitochondrial respiration by nitric oxide inhibition of cytochrome c oxidase. Biochim Biophys Acta. 2001;1504(1):46–57.

    Article  CAS  PubMed  Google Scholar 

  51. Youle RJ, Narendra DP. Mechanisms of mitophagy. Nat Rev Mol Cell Biol. 2011;12(1):9–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Li A, Gao M, Liu B, Qin Y, Chen L, Liu H, Wu H, Gong G. Mitochondrial autophagy: molecular mechanisms and implications for cardiovascular disease. Cell Death Dis. 2022;13(5):444.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Yu J, Nagasu H, Murakami T, Hoang H, Broderick L, Hoffman HM, Horng T. Inflammasome activation leads to Caspase-1-dependent mitochondrial damage and block of mitophagy. Proc Natl Acad Sci USA. 2014;111(43):15514–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Patoli D, Mignotte F, Deckert V, Dusuel A, Dumont A, Rieu A, Jalil A, Van Dongen K, Bourgeois T, Gautier T, et al. Inhibition of mitophagy drives macrophage activation and antibacterial defense during sepsis. J Clin Invest. 2020;130(11):5858–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Dagvadorj J, Mikulska-Ruminska K, Tumurkhuu G, Ratsimandresy RA, Carriere J, Andres AM, Marek-Iannucci S, Song Y, Chen S, Lane M, et al. Recruitment of pro-IL-1alpha to mitochondrial cardiolipin, via shared LC3 binding domain, inhibits mitophagy and drives maximal NLRP3 activation. Proc Natl Acad Sci USA. 2021;118(1):15.

    Article  Google Scholar 

  56. Herzig S, Shaw RJ. AMPK: guardian of metabolism and mitochondrial homeostasis. Nat Rev Mol Cell Biol. 2018;19(2):121–35.

    Article  CAS  PubMed  Google Scholar 

  57. Tadie JM, Bae HB, Deshane JS, Bell CP, Lazarowski ER, Chaplin DD, Thannickal VJ, Abraham E, Zmijewski JW. Toll-like receptor 4 engagement inhibits adenosine 5’-monophosphate-activated protein kinase activation through a high mobility group box 1 protein-dependent mechanism. Mol Med. 2012;18(1):659–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Ip WKE, Hoshi N, Shouval DS, Snapper S, Medzhitov R. Anti-inflammatory effect of IL-10 mediated by metabolic reprogramming of macrophages. Science. 2017;356(6337):513–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Zhong Z, Umemura A, Sanchez-Lopez E, Liang S, Shalapour S, Wong J, He F, Boassa D, Perkins G, Ali SR, et al. NF-kappaB restricts inflammasome activation via elimination of damaged mitochondria. Cell. 2016;164(5):896–910.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Kim MJ, Bae SH, Ryu JC, Kwon Y, Oh JH, Kwon J, Moon JS, Kim K, Miyawaki A, Lee MG, et al. SESN2/sestrin2 suppresses sepsis by inducing mitophagy and inhibiting NLRP3 activation in macrophages. Autophagy. 2016;12(8):1272–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Sun Y, Yao X, Zhang QJ, Zhu M, Liu ZP, Ci B, Xie Y, Carlson D, Rothermel BA, Sun Y, et al. Beclin-1-dependent autophagy protects the heart during sepsis. Circulation. 2018;138(20):2247–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Wang Y, Zhu J, Liu Z, Shu S, Fu Y, Liu Y, Cai J, Tang C, Liu Y, Yin X, et al. The PINK1/PARK2/optineurin pathway of mitophagy is activated for protection in septic acute kidney injury. Redox Biol. 2021;38:101767.

    Article  CAS  PubMed  Google Scholar 

  63. Crouser ED, Julian MW, Huff JE, Struck J, Cook CH. Carbamoyl phosphate synthase-1: a marker of mitochondrial damage and depletion in the liver during sepsis. Crit Care Med. 2006;34(9):2439–46.

    Article  CAS  PubMed  Google Scholar 

  64. Sabouny R, Shutt TE. Reciprocal regulation of mitochondrial fission and fusion. Trends Biochem Sci. 2020;45(7):564–77.

    Article  CAS  PubMed  Google Scholar 

  65. Held NM, Houtkooper RH. Mitochondrial quality control pathways as determinants of metabolic health. BioEssays. 2015;37(8):867–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Tilokani L, Nagashima S, Paupe V, Prudent J. Mitochondrial dynamics: overview of molecular mechanisms. Essays Biochem. 2018;62(3):341–60.

    Article  PubMed  PubMed Central  Google Scholar 

  67. Zhang S, Xu Y, Zhu J, Ma J, Niu Q, Wang X. Carbon monoxide attenuates LPS-induced myocardial dysfunction in rats by regulating the mitochondrial dynamic equilibrium. Eur J Pharmacol. 2020;889:173726.

    Article  CAS  PubMed  Google Scholar 

  68. Gonzalez AS, Elguero ME, Finocchietto P, Holod S, Romorini L, Miriuka SG, Peralta JG, Poderoso JJ, Carreras MC. Abnormal mitochondrial fusion-fission balance contributes to the progression of experimental sepsis. Free Radic Res. 2014;48(7):769–83.

    Article  CAS  PubMed  Google Scholar 

  69. Liu R, Wang SC, Li M, Ma XH, Jia XN, Bu Y, Sun L, Yu KJ. An inhibitor of DRP1 (Mdivi-1) alleviates LPS-induced septic AKI by inhibiting NLRP3 inflammasome activation. Biomed Res Int. 2020;2020:2398420.

    PubMed  PubMed Central  Google Scholar 

  70. Deng S, Zhang L, Mo Y, Huang Y, Li W, Peng Q, Huang L, Ai Y. Mdivi-1 attenuates lipopolysaccharide-induced acute lung injury by inhibiting MAPKs, oxidative stress and apoptosis. Pulm Pharmacol Ther. 2020;62:101918.

    Article  CAS  PubMed  Google Scholar 

  71. Haileselassie B, Mukherjee R, Joshi AU, Napier BA, Massis LM, Ostberg NP, Queliconi BB, Monack D, Bernstein D, Mochly-Rosen D. Drp1/Fis1 interaction mediates mitochondrial dysfunction in septic cardiomyopathy. J Mol Cell Cardiol. 2019;130:160–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Tan Y, Ouyang H, Xiao X, Zhong J, Dong M. Irisin ameliorates septic cardiomyopathy via inhibiting DRP1-related mitochondrial fission and normalizing the JNK-LATS2 signaling pathway. Cell Stress Chaperones. 2019;24(3):595–608.

    Article  PubMed  PubMed Central  Google Scholar 

  73. Norenberg MD, Rao KV. The mitochondrial permeability transition in neurologic disease. Neurochem Int. 2007;50(7–8):983–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Westphal D, Kluck RM, Dewson G. Building blocks of the apoptotic pore: how Bax and Bak are activated and oligomerize during apoptosis. Cell Death Differ. 2014;21(2):196–205.

    Article  CAS  PubMed  Google Scholar 

  75. McArthur K, Whitehead LW, Heddleston JM, Li L, Padman BS, Oorschot V, Geoghegan ND, Chappaz S, Davidson S, San Chin H, et al. BAK/BAX macropores facilitate mitochondrial herniation and mtDNA efflux during apoptosis. Science. 2018;359(6378):eaao6047.

    Article  PubMed  Google Scholar 

  76. Riley JS, Quarato G, Cloix C, Lopez J, O’Prey J, Pearson M, Chapman J, Sesaki H, Carlin LM, Passos JF, et al. Mitochondrial inner membrane permeabilisation enables mtDNA release during apoptosis. EMBO J. 2018;37(17):e99238.

    Article  PubMed  PubMed Central  Google Scholar 

  77. Elmore S. Apoptosis: a review of programmed cell death. Toxicol Pathol. 2007;35(4):495–516.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Li H, Zhu H, Xu CJ, Yuan J. Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell. 1998;94(4):491–501.

    Article  CAS  PubMed  Google Scholar 

  79. Kuwana T, Mackey MR, Perkins G, Ellisman MH, Latterich M, Schneiter R, Green DR, Newmeyer DD. Bid, Bax, and lipids cooperate to form supramolecular openings in the outer mitochondrial membrane. Cell. 2002;111(3):331–42.

    Article  CAS  PubMed  Google Scholar 

  80. Desagher S, Osen-Sand A, Nichols A, Eskes R, Montessuit S, Lauper S, Maundrell K, Antonsson B, Martinou JC. Bid-induced conformational change of Bax is responsible for mitochondrial cytochrome c release during apoptosis. J Cell Biol. 1999;144(5):891–901.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Chung CS, Venet F, Chen Y, Jones LN, Wilson DC, Ayala CA, Ayala A. Deficiency of Bid protein reduces sepsis-induced apoptosis and inflammation, while improving septic survival. Shock. 2010;34(2):150–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Heilig R, Dilucca M, Boucher D, Chen KW, Hancz D, Demarco B, Shkarina K, Broz P. Caspase-1 cleaves Bid to release mitochondrial SMAC and drive secondary necrosis in the absence of GSDMD. Life Sci Alliance. 2020;3(6):e202000735.

    Article  Google Scholar 

  83. Nakahira K, Haspel JA, Rathinam VA, Lee SJ, Dolinay T, Lam HC, Englert JA, Rabinovitch M, Cernadas M, Kim HP, et al. Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nat Immunol. 2011;12(3):222–30.

    Article  CAS  PubMed  Google Scholar 

  84. Larche J, Lancel S, Hassoun SM, Favory R, Decoster B, Marchetti P, Chopin C, Neviere R. Inhibition of mitochondrial permeability transition prevents sepsis-induced myocardial dysfunction and mortality. J Am Coll Cardiol. 2006;48(2):377–85.

    Article  CAS  PubMed  Google Scholar 

  85. Crouser ED, Julian MW, Joshi MS, Bauer JA, Wewers MD, Hart JM, Pfeiffer DR. Cyclosporin A ameliorates mitochondrial ultrastructural injury in the ileum during acute endotoxemia. Crit Care Med. 2002;30(12):2722–8.

    Article  CAS  PubMed  Google Scholar 

  86. Hu Y, Yan JB, Zheng MZ, Song XH, Wang LL, Shen YL, Chen YY. Mitochondrial aldehyde dehydrogenase activity protects against lipopolysaccharide-induced cardiac dysfunction in rats. Mol Med Rep. 2015;11(2):1509–15.

    Article  CAS  PubMed  Google Scholar 

  87. Bernardi P, Gerle C, Halestrap AP, Jonas EA, Karch J, Mnatsakanyan N, Pavlov E, Sheu S-S, Soukas AA. Identity, structure, and function of the mitochondrial permeability transition pore: controversies, consensus, recent advances, and future directions. Cell Death Differ. 2023;30(8):1869–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Bonora M, Giorgi C, Pinton P. Molecular mechanisms and consequences of mitochondrial permeability transition. Nat Rev Mol Cell Biol. 2022;23(4):266–85.

    Article  CAS  PubMed  Google Scholar 

  89. Orrenius S, Gogvadze V, Zhivotovsky B. Mitochondrial oxidative stress: implications for cell death. Annu Rev Pharmacol Toxicol. 2007;47:143–83.

    Article  CAS  PubMed  Google Scholar 

  90. Zorov DB, Juhaszova M, Sollott SJ. Mitochondrial reactive oxygen species (ROS) and ROS-induced ROS release. Physiol Rev. 2014;94(3):909–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Wang S, Moreau F, Chadee K. Gasdermins in innate host defense against entamoeba histolytica and other protozoan parasites. Front Immunol. 2022;13:900553.

    Article  PubMed  PubMed Central  Google Scholar 

  92. Rogers C, Erkes DA, Nardone A, Aplin AE, Fernandes-Alnemri T, Alnemri ES. Gasdermin pores permeabilize mitochondria to augment caspase-3 activation during apoptosis and inflammasome activation. Nat Commun. 2019;10(1):1689.

    Article  PubMed  PubMed Central  Google Scholar 

  93. de Vasconcelos NM, Van Opdenbosch N, Van Gorp H, Parthoens E, Lamkanfi M. Single-cell analysis of pyroptosis dynamics reveals conserved GSDMD-mediated subcellular events that precede plasma membrane rupture. Cell Death Differ. 2019;26(1):146–61.

    Article  PubMed  Google Scholar 

  94. Huang LS, Hong Z, Wu W, Xiong S, Zhong M, Gao X, Rehman J, Malik AB. mtDNA activates cGAS signaling and suppresses the YAP-mediated endothelial cell proliferation program to promote inflammatory injury. Immunity. 2020;52(3):475-486 e475.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Miao R, Jiang C, Chang WY, Zhang H, An J, Ho F, Chen P, Zhang H, Junqueira C, Amgalan D, et al. Gasdermin D permeabilization of mitochondrial inner and outer membranes accelerates and enhances pyroptosis. Immunity. 2023;56(11):2523-2541 e2528.

    Article  CAS  PubMed  Google Scholar 

  96. Lin PH, Lin HY, Kuo CC, Yang LT. N-terminal functional domain of Gasdermin A3 regulates mitochondrial homeostasis via mitochondrial targeting. J Biomed Sci. 2015;22(1):44.

    Article  PubMed  PubMed Central  Google Scholar 

  97. Kondolf HC, D’Orlando DA, Dubyak GR, Abbott DW. Protein engineering reveals that gasdermin A preferentially targets mitochondrial membranes over the plasma membrane during pyroptosis. J Biol Chem. 2023;299(2):102908.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Takeuchi O, Akira S. Pattern recognition receptors and inflammation. Cell. 2010;140(6):805–20.

    Article  CAS  PubMed  Google Scholar 

  99. Nong Y, Wei X, Yu D. Inflammatory mechanisms and intervention strategies for sepsis-induced myocardial dysfunction. Immun Inflamm Dis. 2023;11(5):e860.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Abais JM, Xia M, Zhang Y, Boini KM, Li PL. Redox regulation of NLRP3 inflammasomes: ROS as trigger or effector? Antioxid Redox Signal. 2015;22(13):1111–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Zang QS, Sadek H, Maass DL, Martinez B, Ma L, Kilgore JA, Williams NS, Frantz DE, Wigginton JG, Nwariaku FE, et al. Specific inhibition of mitochondrial oxidative stress suppresses inflammation and improves cardiac function in a rat pneumonia-related sepsis model. Am J Physiol Heart Circ Physiol. 2012;302(9):H1847-1859.

    Article  CAS  PubMed  Google Scholar 

  102. Lowes DA, Thottakam BM, Webster NR, Murphy MP, Galley HF. The mitochondria-targeted antioxidant MitoQ protects against organ damage in a lipopolysaccharide-peptidoglycan model of sepsis. Free Radic Biol Med. 2008;45(11):1559–65.

    Article  CAS  PubMed  Google Scholar 

  103. Xia Y, Cao Y, Sun Y, Hong X, Tang Y, Yu J, Hu H, Ma W, Qin K, Bao R. Calycosin alleviates sepsis-induced acute lung injury via the inhibition of mitochondrial ROS-mediated inflammasome activation. Front Pharmacol. 2021;12:690549.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Zhou R, Tardivel A, Thorens B, Choi I, Tschopp J. Thioredoxin-interacting protein links oxidative stress to inflammasome activation. Nat Immunol. 2010;11(2):136–40.

    Article  CAS  PubMed  Google Scholar 

  105. Juliana C, Fernandes-Alnemri T, Kang S, Farias A, Qin F, Alnemri ES. Non-transcriptional priming and deubiquitination regulate NLRP3 inflammasome activation. J Biol Chem. 2012;287(43):36617–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Bauernfeind F, Bartok E, Rieger A, Franchi L, Nunez G, Hornung V. Cutting edge: reactive oxygen species inhibitors block priming, but not activation, of the NLRP3 inflammasome. J Immunol. 2011;187(2):613–7.

    Article  CAS  PubMed  Google Scholar 

  107. Shimada K, Crother TR, Karlin J, Dagvadorj J, Chiba N, Chen S, Ramanujan VK, Wolf AJ, Vergnes L, Ojcius DM, et al. Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis. Immunity. 2012;36(3):401–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Zhong Z, Liang S, Sanchez-Lopez E, He F, Shalapour S, Lin XJ, Wong J, Ding S, Seki E, Schnabl B, et al. New mitochondrial DNA synthesis enables NLRP3 inflammasome activation. Nature. 2018;560(7717):198–203.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Xian H, Watari K, Sanchez-Lopez E, Offenberger J, Onyuru J, Sampath H, Ying W, Hoffman HM, Shadel GS, Karin M. Oxidized DNA fragments exit mitochondria via mPTP- and VDAC-dependent channels to activate NLRP3 inflammasome and interferon signaling. Immunity. 2022;55(8):1370-1385 e1378.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Nozaki K, Li L, Miao EA. Innate sensors trigger regulated cell death to combat intracellular infection. Annu Rev Immunol. 2022;40:469–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Li X, Thome S, Ma X, Amrute-Nayak M, Finigan A, Kitt L, Masters L, James JR, Shi Y, Meng G, et al. MARK4 regulates NLRP3 positioning and inflammasome activation through a microtubule-dependent mechanism. Nat Commun. 2017;8:15986.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Zhou R, Yazdi AS, Menu P, Tschopp J. A role for mitochondria in NLRP3 inflammasome activation. Nature. 2011;469(7329):221–5.

    Article  CAS  PubMed  Google Scholar 

  113. Chen J, Chen ZJ. PtdIns4P on dispersed trans-Golgi network mediates NLRP3 inflammasome activation. Nature. 2018;564(7734):71–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Magupalli VG, Negro R, Tian Y, Hauenstein AV, Di Caprio G, Skillern W, Deng Q, Orning P, Alam HB, Maliga Z, et al. HDAC6 mediates an aggresome-like mechanism for NLRP3 and pyrin inflammasome activation. Science. 2020;369(6510):eaas8995.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Pandey A, Shen C, Feng S, Man SM. Cell biology of inflammasome activation. Trends Cell Biol. 2021;31(11):924–39.

    Article  CAS  PubMed  Google Scholar 

  116. Misawa T, Takahama M, Kozaki T, Lee H, Zou J, Saitoh T, Akira S. Microtubule-driven spatial arrangement of mitochondria promotes activation of the NLRP3 inflammasome. Nat Immunol. 2013;14(5):454–60.

    Article  CAS  PubMed  Google Scholar 

  117. Subramanian N, Natarajan K, Clatworthy MR, Wang Z, Germain RN. The adaptor MAVS promotes NLRP3 mitochondrial localization and inflammasome activation. Cell. 2013;153(2):348–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Iyer SS, He Q, Janczy JR, Elliott EI, Zhong Z, Olivier AK, Sadler JJ, Knepper-Adrian V, Han R, Qiao L, et al. Mitochondrial cardiolipin is required for Nlrp3 inflammasome activation. Immunity. 2013;39(2):311–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Elliott EI, Miller AN, Banoth B, Iyer SS, Stotland A, Weiss JP, Gottlieb RA, Sutterwala FS, Cassel SL. Cutting edge: mitochondrial assembly of the NLRP3 inflammasome complex is initiated at priming. J Immunol. 2018;200(9):3047–52.

    Article  CAS  PubMed  Google Scholar 

  120. Park S, Juliana C, Hong S, Datta P, Hwang I, Fernandes-Alnemri T, Yu JW, Alnemri ES. The mitochondrial antiviral protein MAVS associates with NLRP3 and regulates its inflammasome activity. J Immunol. 2013;191(8):4358–66.

    Article  CAS  PubMed  Google Scholar 

  121. Franchi L, Eigenbrod T, Munoz-Planillo R, Ozkurede U, Kim YG, Arindam C, Gale M Jr, Silverman RH, Colonna M, Akira S, et al. Cytosolic double-stranded RNA activates the NLRP3 inflammasome via MAVS-induced membrane permeabilization and K+ efflux. J Immunol. 2014;193(8):4214–22.

    Article  CAS  PubMed  Google Scholar 

  122. Ren Z, Ding T, Zuo Z, Xu Z, Deng J, Wei Z. Regulation of MAVS expression and signaling function in the antiviral innate immune response. Front Immunol. 2020;11:1030.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Andreeva L, David L, Rawson S, Shen C, Pasricha T, Pelegrin P, Wu H. NLRP3 cages revealed by full-length mouse NLRP3 structure control pathway activation. Cell. 2021;184(26):6299-6312 e6222.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Zhang Z, Meszaros G, He WT, Xu Y, de Fatima MH, Mailly L, Mihlan M, Liu Y, Puig Gamez M, Goginashvili A, et al. Protein kinase D at the Golgi controls NLRP3 inflammasome activation. J Exp Med. 2017;214(9):2671–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Xiao L, Magupalli VG, Wu H. Cryo-EM structures of the active NLRP3 inflammasome disc. Nature. 2023;613(7944):595–600.

    Article  CAS  PubMed  Google Scholar 

  126. Fu J, Wu H. Structural mechanisms of NLRP3 inflammasome assembly and activation. Annu Rev Immunol. 2023;41:301–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Ablasser A, Chen ZJ. cGAS in action: Expanding roles in immunity and inflammation. Science. 2019;363(6431):eaat8657.

    Article  CAS  PubMed  Google Scholar 

  128. Xian H, Karin M. Oxidized mitochondrial DNA: a protective signal gone awry. Trends Immunol. 2023;44(3):188–200.

    Article  CAS  PubMed  Google Scholar 

  129. Gehrke N, Mertens C, Zillinger T, Wenzel J, Bald T, Zahn S, Tuting T, Hartmann G, Barchet W. Oxidative damage of DNA confers resistance to cytosolic nuclease TREX1 degradation and potentiates STING-dependent immune sensing. Immunity. 2013;39(3):482–95.

    Article  CAS  PubMed  Google Scholar 

  130. Nakahira K, Kyung SY, Rogers AJ, Gazourian L, Youn S, Massaro AF, Quintana C, Osorio JC, Wang Z, Zhao Y et al. Circulating mitochondrial DNA in patients in the ICU as a marker of mortality: derivation and validation. PLoS Med 2013;10(12):e1001577; discussion e1001577.

  131. Wang L, Zhou W, Wang K, He S, Chen Y. Predictive value of circulating plasma mitochondrial DNA for Sepsis in the emergency department: observational study based on the Sepsis-3 definition. BMC Emerg Med. 2020;20(1):25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Schneck E, Edinger F, Hecker M, Sommer N, Pak O, Weissmann N, Hecker A, Reichert M, Markmann M, Sander M, et al. Blood levels of free-circulating mitochondrial DNA in septic shock and postsurgical systemic inflammation and its influence on coagulation: a secondary analysis of a prospective observational study. J Clin Med. 2020;9(7):2056.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Liu Q, Wu J, Zhang X, Li X, Wu X, Zhao Y, Ren J. Circulating mitochondrial DNA-triggered autophagy dysfunction via STING underlies sepsis-related acute lung injury. Cell Death Dis. 2021;12(7):673.

    Article  PubMed  PubMed Central  Google Scholar 

  134. Hu Q, Ren H, Li G, Wang D, Zhou Q, Wu J, Zheng J, Huang J, Slade DA, Wu X, et al. STING-mediated intestinal barrier dysfunction contributes to lethal sepsis. EBioMedicine. 2019;41:497–508.

    Article  PubMed  PubMed Central  Google Scholar 

  135. Xu L, Li M, Yang Y, Zhang C, Xie Z, Tang J, Shi Z, Chen S, Li G, Gu Y, et al. Salmonella induces the cGAS-STING-dependent type I interferon response in murine macrophages by triggering mtDNA release. MBio. 2022;13(3):e0363221.

    Article  PubMed  Google Scholar 

  136. Zhang RX, Kang R, Tang DL. STING1 in sepsis: mechanisms, functions, and implications. Chin J Traumatol. 2022;25(1):1–10.

    Article  CAS  PubMed  Google Scholar 

  137. Hemmi H, Takeuchi O, Kawai T, Kaisho T, Sato S, Sanjo H, Matsumoto M, Hoshino K, Wagner H, Takeda K, et al. A Toll-like receptor recognizes bacterial DNA. Nature. 2000;408(6813):740–5.

    Article  CAS  PubMed  Google Scholar 

  138. Lund J, Sato A, Akira S, Medzhitov R, Iwasaki A. Toll-like receptor 9-mediated recognition of Herpes simplex virus-2 by plasmacytoid dendritic cells. J Exp Med. 2003;198(3):513–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Zhang Q, Raoof M, Chen Y, Sumi Y, Sursal T, Junger W, Brohi K, Itagaki K, Hauser CJ. Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature. 2010;464(7285):104–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Tsuji N, Tsuji T, Ohashi N, Kato A, Fujigaki Y, Yasuda H. Role of Mitochondrial DNA in septic AKI via toll-like receptor 9. J Am Soc Nephrol. 2016;27(7):2009–20.

    Article  CAS  PubMed  Google Scholar 

  141. Yasuda H, Leelahavanichkul A, Tsunoda S, Dear JW, Takahashi Y, Ito S, Hu X, Zhou H, Doi K, Childs R, et al. Chloroquine and inhibition of Toll-like receptor 9 protect from sepsis-induced acute kidney injury. Am J Physiol Renal Physiol. 2008;294(5):F1050–8.

    Article  CAS  PubMed  Google Scholar 

  142. Plitas G, Burt BM, Nguyen HM, Bamboat ZM, DeMatteo RP. Toll-like receptor 9 inhibition reduces mortality in polymicrobial sepsis. J Exp Med. 2008;205(6):1277–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Liu J, Zhou G, Wang X, Liu D. Metabolic reprogramming consequences of sepsis: adaptations and contradictions. Cell Mol Life Sci. 2022;79(8):456.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Liu C, Wei W, Huang Y, Fu P, Zhang L, Zhao Y. Metabolic reprogramming in septic acute kidney injury: pathogenesis and therapeutic implications. Metabolism. 2024;158:155974.

    Article  CAS  PubMed  Google Scholar 

  145. Van Wyngene L, Vandewalle J, Libert C. Reprogramming of basic metabolic pathways in microbial sepsis: therapeutic targets at last? EMBO Mol Med. 2018;10(8):e8712.

    Article  PubMed  PubMed Central  Google Scholar 

  146. Pan T, Sun S, Chen Y, Tian R, Chen E, Tan R, Wang X, Liu Z, Liu J, Qu H. Immune effects of PI3K/Akt/HIF-1alpha-regulated glycolysis in polymorphonuclear neutrophils during sepsis. Crit Care. 2022;26(1):29.

    Article  PubMed  PubMed Central  Google Scholar 

  147. Tan C, Gu J, Chen H, Li T, Deng H, Liu K, Liu M, Tan S, Xiao Z, Zhang H, et al. Inhibition of aerobic glycolysis promotes neutrophil to influx to the infectious site via CXCR2 in sepsis. Shock. 2020;53(1):114–23.

    Article  CAS  PubMed  Google Scholar 

  148. Hotchkiss RS, Swanson PE, Freeman BD, Tinsley KW, Cobb JP, Matuschak GM, Buchman TG, Karl IE. Apoptotic cell death in patients with sepsis, shock, and multiple organ dysfunction. Crit Care Med. 1999;27(7):1230–51.

    Article  CAS  PubMed  Google Scholar 

  149. Singer M, De Santis V, Vitale D, Jeffcoate W. Multiorgan failure is an adaptive, endocrine-mediated, metabolic response to overwhelming systemic inflammation. Lancet. 2004;364(9433):545–8.

    Article  PubMed  Google Scholar 

  150. Brealey D, Brand M, Hargreaves I, Heales S, Land J, Smolenski R, Davies NA, Cooper CE, Singer M. Association between mitochondrial dysfunction and severity and outcome of septic shock. Lancet. 2002;360(9328):219–23.

    Article  CAS  PubMed  Google Scholar 

  151. Dhanasekaran A, Kotamraju S, Kalivendi SV, Matsunaga T, Shang T, Keszler A, Joseph J, Kalyanaraman B. Supplementation of endothelial cells with mitochondria-targeted antioxidants inhibit peroxide-induced mitochondrial iron uptake, oxidative damage, and apoptosis. J Biol Chem. 2004;279(36):37575–87.

    Article  CAS  PubMed  Google Scholar 

  152. McCormick B, Lowes DA, Colvin L, Torsney C, Galley HF. MitoVitE, a mitochondria-targeted antioxidant, limits paclitaxel-induced oxidative stress and mitochondrial damage in vitro, and paclitaxel-induced mechanical hypersensitivity in a rat pain model. Br J Anaesth. 2016;117(5):659–66.

    Article  CAS  PubMed  Google Scholar 

  153. Gioscia-Ryan RA, LaRocca TJ, Sindler AL, Zigler MC, Murphy MP, Seals DR. Mitochondria-targeted antioxidant (MitoQ) ameliorates age-related arterial endothelial dysfunction in mice. J Physiol. 2014;592(12):2549–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Kalyanaraman B, Cheng G, Hardy M, You M. OXPHOS-targeting drugs in oncology: new perspectives. Expert Opin Ther Targets. 2023;27(10):939–52.

    Article  CAS  PubMed  Google Scholar 

  155. Zhang S, Zhou Q, Li Y, Zhang Y, Wu Y. MitoQ modulates lipopolysaccharide-induced intestinal barrier dysfunction via regulating Nrf2 signaling. Mediat Inflamm. 2020;2020:3276148.

    Article  Google Scholar 

  156. Supinski GS, Murphy MP, Callahan LA. MitoQ administration prevents endotoxin-induced cardiac dysfunction. Am J Physiol Regul Integr Comp Physiol. 2009;297(4):R1095-1102.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Supinski GS, Schroder EA, Wang L, Morris AJ, Callahan LAP. Mitoquinone mesylate (MitoQ) prevents sepsis-induced diaphragm dysfunction. J Appl Physiol (1985). 2021;131(2):778–87.

    Article  CAS  PubMed  Google Scholar 

  158. Smith RA, Porteous CM, Coulter CV, Murphy MP. Selective targeting of an antioxidant to mitochondria. Eur J Biochem. 1999;263(3):709–16.

    Article  CAS  PubMed  Google Scholar 

  159. Lowes DA, Webster NR, Murphy MP, Galley HF. Antioxidants that protect mitochondria reduce interleukin-6 and oxidative stress, improve mitochondrial function, and reduce biochemical markers of organ dysfunction in a rat model of acute sepsis. Br J Anaesth. 2013;110(3):472–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Trnka J, Blaikie FH, Smith RA, Murphy MP. A mitochondria-targeted nitroxide is reduced to its hydroxylamine by ubiquinol in mitochondria. Free Radic Biol Med. 2008;44(7):1406–19.

    Article  CAS  PubMed  Google Scholar 

  161. Arulkumaran N, Pollen SJ, Tidswell R, Gaupp C, Peters VBM, Stanzani G, Snow TAC, Duchen MR, Singer M. Selective mitochondrial antioxidant MitoTEMPO reduces renal dysfunction and systemic inflammation in experimental sepsis in rats. Br J Anaesth. 2021;127(4):577–86.

    Article  CAS  PubMed  Google Scholar 

  162. Navas LE, Carnero A. NAD(+) metabolism, stemness, the immune response, and cancer. Signal Transduct Target Ther. 2021;6(1):2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Liaudet L, Mabley JG, Soriano FG, Pacher P, Marton A, Hasko G, Szabo C. Inosine reduces systemic inflammation and improves survival in septic shock induced by cecal ligation and puncture. Am J Respir Crit Care Med. 2001;164(7):1213–20.

    Article  CAS  PubMed  Google Scholar 

  164. Cao T, Ni R, Ding W, Ji X, Fan GC, Zhang Z, Peng T. Nicotinamide mononucleotide as a therapeutic agent to alleviate multi-organ failure in sepsis. J Transl Med. 2023;21(1):883.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Hong G, Zheng D, Zhang L, Ni R, Wang G, Fan GC, Lu Z, Peng T. Administration of nicotinamide riboside prevents oxidative stress and organ injury in sepsis. Free Radic Biol Med. 2018;123:125–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Ye M, Zhao Y, Wang Y, Xie R, Tong Y, Sauer JD, Gong S. NAD(H)-loaded nanoparticles for efficient sepsis therapy via modulating immune and vascular homeostasis. Nat Nanotechnol. 2022;17(8):880–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Ryu D, Mouchiroud L, Andreux PA, Katsyuba E, Moullan N, Nicolet-Dit-Felix AA, Williams EG, Jha P, Lo Sasso G, Huzard D, et al. Urolithin A induces mitophagy and prolongs lifespan in C. elegans and increases muscle function in rodents. Nat Med. 2016;22(8):879–88.

    Article  CAS  PubMed  Google Scholar 

  168. Yang Y, Hu Q, Kang H, Li J, Zhao X, Zhu L, Tang W, Wan M. Urolithin A protects severe acute pancreatitis-associated acute cardiac injury by regulating mitochondrial fatty acid oxidative metabolism in cardiomyocytes. MedComm (2020). 2023;4(6):e459.

    CAS  PubMed  Google Scholar 

  169. Abdelazeem KNM, Kalo MZ, Beer-Hammer S, Lang F. The gut microbiota metabolite urolithin A inhibits NF-kappaB activation in LPS stimulated BMDMs. Sci Rep. 2021;11(1):7117.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Liu S, D’Amico D, Shankland E, Bhayana S, Garcia JM, Aebischer P, Rinsch C, Singh A, Marcinek DJ. Effect of urolithin a supplementation on muscle endurance and mitochondrial health in older adults: a randomized clinical trial. JAMA Netw Open. 2022;5(1):e2144279.

    Article  PubMed  PubMed Central  Google Scholar 

  171. Andreux PA, Blanco-Bose W, Ryu D, Burdet F, Ibberson M, Aebischer P, Auwerx J, Singh A, Rinsch C. The mitophagy activator urolithin A is safe and induces a molecular signature of improved mitochondrial and cellular health in humans. Nat Metab. 2019;1(6):595–603.

    Article  CAS  PubMed  Google Scholar 

  172. Zhu P, Chen Y, Wang J, Lin G, Wang R, Que Y, Zhou J, Xu G, Luo J, Du Y. Receptor-interacting protein kinase 3 suppresses mitophagy activation via the yes-associated protein/transcription factor EB pathways in septic cardiomyopathy. Front Cardiovasc Med. 2022;9:856041.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Wang Y, Jasper H, Toan S, Muid D, Chang X, Zhou H. Mitophagy coordinates the mitochondrial unfolded protein response to attenuate inflammation-mediated myocardial injury. Redox Biol. 2021;45:102049.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Jiao P, Wang Y, Ren G, Chu D, Li Y, Yang Y, Sang T. Urolithin A exerts a protective effect on lipopolysaccharide-induced acute lung injury by regulating HMGB1-mediated MAPK and NF-kappaB signaling pathways. Naunyn Schmiedebergs Arch Pharmacol. 2024;397(8):5765–77.

    Article  CAS  PubMed  Google Scholar 

  175. Libert C, Ayala A, Bauer M, Cavaillon JM, Deutschman C, Frostell C, Knapp S, Kozlov AV, Wang P, Osuchowski MF, et al. Part II: minimum quality threshold in preclinical sepsis studies (MQTiPSS) for types of infections and organ dysfunction endpoints. Shock. 2019;51(1):23–32.

    Article  PubMed  PubMed Central  Google Scholar 

  176. Joffre J, Hellman J, Ince C, Ait-Oufella H. Endothelial responses in sepsis. Am J Respir Crit Care Med. 2020;202(3):361–70.

    Article  CAS  PubMed  Google Scholar 

  177. Cassidy-Stone A, Chipuk JE, Ingerman E, Song C, Yoo C, Kuwana T, Kurth MJ, Shaw JT, Hinshaw JE, Green DR, et al. Chemical inhibition of the mitochondrial division dynamin reveals its role in Bax/Bak-dependent mitochondrial outer membrane permeabilization. Dev Cell. 2008;14(2):193–204.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Manczak M, Kandimalla R, Yin X, Reddy PH. Mitochondrial division inhibitor 1 reduces dynamin-related protein 1 and mitochondrial fission activity. Hum Mol Genet. 2019;28(2):177–99.

    Article  CAS  PubMed  Google Scholar 

  179. Zhang Q, Liu Z, Huang X, Heng X, Wu J, Chen Z, Guo X, Fan J, Huang Q. Mdivi-1 alleviates sepsis-induced liver injury by inhibiting sting signaling activation. Shock. 2024;62(1):95–102.

    Article  CAS  PubMed  Google Scholar 

  180. Fu Q, Zhang YB, Shi CX, Jiang M, Lu K, Fu ZH, Ruan JP, Wu J, Gu XP. GSDMD/Drp1 signaling pathway mediates hippocampal synaptic damage and neural oscillation abnormalities in a mouse model of sepsis-associated encephalopathy. J Neuroinflamm. 2024;21(1):96.

    Article  CAS  Google Scholar 

  181. Haileselassie B, Joshi AU, Minhas PS, Mukherjee R, Andreasson KI, Mochly-Rosen D. Mitochondrial dysfunction mediated through dynamin-related protein 1 (Drp1) propagates impairment in blood brain barrier in septic encephalopathy. J Neuroinflammation. 2020;17(1):36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. de Paiva CS, Pflugfelder SC, Ng SM, Akpek EK. Topical cyclosporine A therapy for dry eye syndrome. Cochrane Database Syst Rev. 2019;9(9):CD010051.

    PubMed  Google Scholar 

  183. Molnar AO, Fergusson D, Tsampalieros AK, Bennett A, Fergusson N, Ramsay T, Knoll GA. Generic immunosuppression in solid organ transplantation: systematic review and meta-analysis. BMJ. 2015;350:h3163.

    Article  PubMed  PubMed Central  Google Scholar 

  184. Luna-Sanchez M, Bianchi P, Quintana A. Mitochondria-induced immune response as a trigger for neurodegeneration: a pathogen from within. Int J Mol Sci. 2021;22(16):8523.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Liddicoat AM, Lavelle EC. Modulation of innate immunity by cyclosporine A. Biochem Pharmacol. 2019;163:472–80.

    Article  CAS  PubMed  Google Scholar 

  186. Xiao Z, Jia B, Zhao X, Bi S, Meng W. Attenuation of lipopolysaccharide-induced acute lung injury by cyclosporine-A via suppression of mitochondrial DNA. Med Sci Monit. 2018;24:7682–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Fauvel H, Marchetti P, Obert G, Joulain O, Chopin C, Formstecher P, Neviere R. Protective effects of cyclosporin A from endotoxin-induced myocardial dysfunction and apoptosis in rats. Am J Respir Crit Care Med. 2002;165(4):449–55.

    Article  PubMed  Google Scholar 

  188. Joshi MS, Julian MW, Huff JE, Bauer JA, Xia Y, Crouser ED. Calcineurin regulates myocardial function during acute endotoxemia. Am J Respir Crit Care Med. 2006;173(9):999–1007.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Flory J, Lipska K. Metformin in 2019. JAMA. 2019;321(19):1926–7.

    Article  PubMed  PubMed Central  Google Scholar 

  190. Lv Z, Guo Y. Metformin and its benefits for various diseases. Front Endocrinol (Lausanne). 2020;11:191.

    Article  PubMed  Google Scholar 

  191. Liu Z, Bone N, Jiang S, Park DW, Tadie JM, Deshane J, Rodriguez CA, Pittet JF, Abraham E, Zmijewski JW. AMP-activated protein kinase and glycogen synthase kinase 3beta modulate the severity of sepsis-induced lung injury. Mol Med. 2016;21(1):937–50.

    Article  PubMed  Google Scholar 

  192. Fan SY, Zhao ZC, Liu XL, Peng YG, Zhu HM, Yan SF, Liu YJ, Xie Q, Jiang Y, Zeng SZ. Metformin mitigates sepsis-induced acute lung injury and inflammation in young mice by suppressing the S100A8/A9-NLRP3-IL-1beta signaling pathway. J Inflamm Res. 2024;17:3785–99.

    Article  PubMed  PubMed Central  Google Scholar 

  193. Tang G, Yang H, Chen J, Shi M, Ge L, Ge X, Zhu G. Metformin ameliorates sepsis-induced brain injury by inhibiting apoptosis, oxidative stress and neuroinflammation via the PI3K/Akt signaling pathway. Oncotarget. 2017;8(58):97977–89.

    Article  PubMed  PubMed Central  Google Scholar 

  194. Liang H, Song H, Zhang X, Song G, Wang Y, Ding X, Duan X, Li L, Sun T, Kan Q. Metformin attenuated sepsis-related liver injury by modulating gut microbiota. Emerg Microbes Infect. 2022;11(1):815–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Doenyas-Barak K, Beberashvili I, Marcus R, Efrati S. Lactic acidosis and severe septic shock in metformin users: a cohort study. Crit Care. 2016;20:10.

    Article  PubMed  PubMed Central  Google Scholar 

  196. Green JP, Berger T, Garg N, Suarez A, Hagar Y, Radeos MS, Panacek EA. Impact of metformin use on the prognostic value of lactate in sepsis. Am J Emerg Med. 2012;30(9):1667–73.

    Article  PubMed  PubMed Central  Google Scholar 

  197. Jochmans S, Alphonsine JE, Chelly J, Vong LVP, Sy O, Rolin N, Ellrodt O, Monchi M, Vinsonneau C. Does metformin exposure before ICU stay have any impact on patients’ outcome? A retrospective cohort study of diabetic patients. Ann Intensive Care. 2017;7(1):116.

    Article  PubMed  PubMed Central  Google Scholar 

  198. van Vught LA, Scicluna BP, Hoogendijk AJ, Wiewel MA, Klein Klouwenberg PM, Cremer OL, Horn J, Nurnberg P, Bonten MM, Schultz MJ, et al. Association of diabetes and diabetes treatment with the host response in critically ill sepsis patients. Crit Care. 2016;20(1):252.

    Article  PubMed  PubMed Central  Google Scholar 

  199. Park J, Hwang SY, Jo IJ, Jeon K, Suh GY, Lee TR, Yoon H, Cha WC, Sim MS, Carriere KC, et al. Impact of metformin use on lactate kinetics in patients with severe sepsis and septic shock. Shock. 2017;47(5):582–7.

    Article  CAS  PubMed  Google Scholar 

  200. Liang H, Ding X, Li L, Wang T, Kan Q, Wang L, Sun T. Association of preadmission metformin use and mortality in patients with sepsis and diabetes mellitus: a systematic review and meta-analysis of cohort studies. Crit Care. 2019;23(1):50.

    Article  PubMed  PubMed Central  Google Scholar 

  201. Yang Q, Zheng J, Chen W, Chen X, Wen D, Chen W, Xiong X, Zhang Z. Association between preadmission metformin use and outcomes in intensive care unit patients with sepsis and type 2 diabetes: a cohort study. Front Med (Lausanne). 2021;8:640785.

    Article  PubMed  Google Scholar 

  202. Foretz M, Guigas B, Viollet B. Metformin: update on mechanisms of action and repurposing potential. Nat Rev Endocrinol. 2023;19(8):460–76.

    Article  CAS  PubMed  Google Scholar 

  203. Howell JJ, Hellberg K, Turner M, Talbott G, Kolar MJ, Ross DS, Hoxhaj G, Saghatelian A, Shaw RJ, Manning BD. Metformin inhibits hepatic mTORC1 signaling via dose-dependent mechanisms involving AMPK and the TSC complex. Cell Metab. 2017;25(2):463–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Xian H, Liu Y, Rundberg Nilsson A, Gatchalian R, Crother TR, Tourtellotte WG, Zhang Y, Aleman-Muench GR, Lewis G, Chen W, et al. Metformin inhibition of mitochondrial ATP and DNA synthesis abrogates NLRP3 inflammasome activation and pulmonary inflammation. Immunity. 2021;54(7):1463-1477 e1411.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Jager S, Handschin C, St-Pierre J, Spiegelman BM. AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1alpha. Proc Natl Acad Sci USA. 2007;104(29):12017–22.

    Article  PubMed  PubMed Central  Google Scholar 

  206. Kim J, Kwak HJ, Cha JY, Jeong YS, Rhee SD, Kim KR, Cheon HG. Metformin suppresses lipopolysaccharide (LPS)-induced inflammatory response in murine macrophages via activating transcription factor-3 (ATF-3) induction. J Biol Chem. 2014;289(33):23246–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  207. Wu W, Wang S, Liu Q, Shan T, Wang Y. Metformin protects against lps-induced intestinal barrier dysfunction by activating AMPK pathway. Mol Pharm. 2018;15(8):3272–84.

    Article  CAS  PubMed  Google Scholar 

  208. Ma T, Tian X, Zhang B, Li M, Wang Y, Yang C, Wu J, Wei X, Qu Q, Yu Y, et al. Low-dose metformin targets the lysosomal AMPK pathway through PEN2. Nature. 2022;603(7899):159–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  209. Cortes M, Brischetto A, Martinez-Campanario MC, Ninfali C, Dominguez V, Fernandez S, Celis R, Esteve-Codina A, Lozano JJ, Sidorova J, et al. Inflammatory macrophages reprogram to immunosuppression by reducing mitochondrial translation. Nat Commun. 2023;14(1):7471.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

Figures used in this review are made in BioRender.com.

Funding

This work is financially supported by MOE Tier2 and Tier1 (A-8000985 and A-8000412) grants from the Ministry of Education (MOE), Singapore, awarded to Y-C. Liou.

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Author notes

  1. Dongxue Hua and Harshini Sheeja Prabhakaran contributed equally to this work.

Authors and Affiliations

  1. Department of Biological Sciences, Faculty of Science, National University of Singapore, Singapore, 117543, Singapore

    Dongxue Hu, Harshini Sheeja Prabhakaran & Yih-Cherng Liou

  2. Integrative Sciences and Engineering Programme, NUS Graduate School, National University of Singapore, Singapore, 119077, Singapore

    Yih-Cherng Liou

  3. Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China

    Yuan-Yuan Zhang

  4. State Key Laboratory of Trauma, Burn and Combined Injury, Institute of Burn Research, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China

    Gaoxing Luo & Weifeng He

  5. Chongqing Key Laboratory for Disease Proteomics, Chongqing, 400038, China

    Gaoxing Luo & Weifeng He

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Contributions

Dongxue Hu and Harshini Sheeja Prabhakaran contributed to the data collection of the article. Dongxue Hu, Harshini Sheeja Prabhakaran, Weifeng He, and Yih-Cherng Liou contributed to the conception, preparation and organization of this article. Yuan-Yuan Zhang and Gaoxing Luo contributed to the organization and constructive discussions. Weifeng He and Yih-Cherng Liou revised the draft of the manuscript.

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Hu, D., Sheeja Prabhakaran, H., Zhang, YY. et al. Mitochondrial dysfunction in sepsis: mechanisms and therapeutic perspectives. Crit Care 28, 292 (2024). https://doi.org/10.1186/s13054-024-05069-w

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Keywords

Critical Care

ISSN: 1364-8535