Temporal increase of platelet mitochondrial respiration is negatively associated with clinical outcome in patients with sepsis
© Sjövall et al.; licensee BioMed Central Ltd. 2010
Received: 17 September 2010
Accepted: 24 November 2010
Published: 24 November 2010
Mitochondrial dysfunction has been suggested as a contributing factor to the pathogenesis of sepsis-induced multiple organ failure. Also, restoration of mitochondrial function, known as mitochondrial biogenesis, has been implicated as a key factor for the recovery of organ function in patients with sepsis. Here we investigated temporal changes in platelet mitochondrial respiratory function in patients with sepsis during the first week after disease onset.
Platelets were isolated from blood samples taken from 18 patients with severe sepsis or septic shock within 48 hours of their admission to the intensive care unit. Subsequent samples were taken on Day 3 to 4 and Day 6 to 7. Eighteen healthy blood donors served as controls. Platelet mitochondrial function was analyzed by high-resolution respirometry. Endogenous respiration of viable, intact platelets suspended in their own plasma or phosphate-buffered saline (PBS) glucose was determined. Further, in order to investigate the role of different dehydrogenases and respiratory complexes as well as to evaluate maximal respiratory activity of the mitochondria, platelets were permeabilized and stimulated with complex-specific substrates and inhibitors.
Platelets suspended in their own septic plasma exhibited increased basal non-phosphorylating respiration (state 4) compared to controls and to platelets suspended in PBS glucose. In parallel, there was a substantial increase in respiratory capacity of the electron transfer system from Day 1 to 2 to Day 6 to 7 as well as compared to controls in both intact and permeabilized platelets oxidizing Complex I and/or II-linked substrates. No inhibition of respiratory complexes was detected in septic patients compared to controls. Non-survivors, at 90 days, had a more elevated respiratory capacity at Day 6 to 7 as compared to survivors. Cytochrome c increased over the time interval studied but no change in mitochondrial DNA was detected.
The results indicate the presence of a soluble plasma factor in the initial stage of sepsis inducing uncoupling of platelet mitochondria without inhibition of the electron transfer system. The mitochondrial uncoupling was paralleled by a gradual and substantial increase in respiratory capacity. This may reflect a compensatory response to severe sepsis or septic shock, that was most pronounced in non-survivors, likely correlating to the severity of the septic insult.
Multiple organ failure (MOF) is the leading cause of death in patients with severe sepsis and septic shock . The cause of MOF is largely unexplained and the pathogenesis is likely complex. Since the failing organs do not undergo necrosis or apoptosis to any large extent , there is a possibility of full recovery with supportive treatment.
Evidence that mitochondrial alterations contribute to the pathogenesis of MOF has been gathered in animal as well as human studies (reviewed in ) although differences exist depending on the tissue studied . Restoration of mitochondrial function has also been suggested as a prerequisite in recovery from MOF. Initial depletion of mitochondrial DNA (mtDNA) and subsequent activation of mitochondrial biogenic factors and restoration of mtDNA copy number were seen in a murine model of sepsis  and recently, increased transcripts of mitochondrial biogenetic markers was associated with survival in patients with severe sepsis and septic shock .
Mitochondria are unique in that they contain their own genome that is maternally inherited. Compared to nuclear DNA, mtDNA is more prone to damage because the DNA is not bound to histones and has reduced capacity of DNA repair . A fall in mtDNA in mononuclear cells was recently shown in patients with sepsis  and a temporal increase of mtDNA in blood cells from septic patients has been associated with improved outcome .
Platelets are anucleated cells that contain two to eight mitochondria per cell  with their main function in the process of coagulation. Recently, they have been shown to play a role in innate immunity, containing toll-like receptors and interplaying with other immune cells . Further, platelet mitochondria have been proposed to serve as a marker for changes in mitochondrial function occurring in senescence and age-related diseases [12–14].
Although mitochondrial biogenesis seems to be triggered early on in sepsis the temporal evolution or functional outcome has not been avidly studied. This is in part due to the ethical and practical problems of obtaining adequate mitochondrial samples from vital organs in critically ill patients. In order to address this question we examined changes in platelet mitochondrial respiratory function during the first week in patients with severe sepsis or septic shock and evaluated how these changes correlated with clinical parameters, severity scores and mortality. Using high-resolution respirometry we analyzed integrated mitochondrial function in both intact platelets with preserved intra- and extracellular environment as well as the contribution of individual respiratory complexes in permeabilized cells. By evaluating platelet mitochondrial function in the presence or absence of the patients' own plasma we addressed the possible influence of soluble factors affecting respiratory capacity.
Preliminary data of this study have been presented at the annual International Sepsis Forum meeting 2010 .
Materials and methods
This study was approved by the scientific ethical committee of Copenhagen County, Denmark (H-C-2008-023) and the regional ethical review board of Lund, Sweden (113/2008). Patients were recruited from the intensive care units (ICU) of Lund University Hospital and Copenhagen University Hospital, Rigshospitalet. Written, informed consent was obtained from the patient or next of kin. In Denmark, consent from the patient's primary health care physician was also required if the patient was unconscious. Eighteen patients with severe sepsis or septic shock, as previously defined , were included within 48 h after their admission to the ICU. Diagnosis of sepsis should have been made no more than 24 h prior to ICU admission. Patients with platelet count <10 × 109/L, pregnancy, known mitochondrial disease or hematological malignancy were excluded. Blood samples were taken at three different time points during the first week following admission to the ICU; within the first 48 h (Day 1 to 2), on Day 3 to 4 and Day 6 to 7. If a patient received platelet transfusion a minimum of six hours had to pass before blood sampling. Eighteen healthy blood donors served as controls following written, informed consent.
Chemicals and sample preparation
All chemicals were purchased from Sigma-Aldrich (St Louis, MO, USA) if not stated otherwise. In patients, a maximal volume of 40 mL of blood was drawn from an existing arterial line in K2EDTA tubes (Vacuette®, Greiner Bio-One GmbH, Kremmünster, Austria). In controls, blood samples were taken at the time of planned donation via venous puncture in K2EDTA tubes. Platelets were freshly prepared by centrifugation 10 to 15 minutes at 300 × g resulting in a platelet-rich plasma (PRP). This PRP was collected and centrifuged for five minutes at 4,600 × g producing a close to cell-free plasma and a platelet pellet. The pellet was resuspended in 1 to 3 mL of plasma by gentle pipeting to obtain a highly enriched PRP.
Measurement of mitochondrial respiration was performed in a high-resolution oxygraph (Oxygraph-2k Oroboros Instruments, Innsbruck, Austria ) at a constant temperature of 37°C. Platelets were suspended in the 2 mL glass chamber at a concentration of 50 to 200 × 106/mL. Calibration with air-saturated Millipore water was performed daily. For experiments in intact cells, platelets were suspended in either phosphate buffered saline (PBS) with addition of 5 mM glucose or in their own plasma. For respiration measurements in permeabilized cells, platelets were suspended in a mitochondrial respiration medium (MiR05) containing sucrose 110 mM, HEPES 20 mM, taurine 20 mM, K-lactobionate 60 mM, MgCl2 3 mM, KH2PO4 10 mM, EGTA 0.5 mM, BSA 1 g/l, pH 7.1 . Oxygen solubility factors relative to pure water were set to 0.92 for MiR05 and PBS glucose and 0.89 for plasma. Data were collected using software displaying real-time oxygen concentration and oxygen flux, that is, the negative time derivative of oxygen concentration (DatLab software 4.3, Oroboros Instruments, Innsbruck, Austria).
Experimental protocol for intact cells
Respiration was first allowed to stabilize without any additions at a routine state, that is, in the physiological coupling state controlled by cellular energy demands on oxidative phosphorylation (OXPHOS). Then the ATP synthase inhibitor oligomycin was added to reveal respiration independent of ADP phosphorylation (oligomycin-induced state 4, henceforth denoted as state 4). To evaluate maximal capacity of the electron transfer system (ETS) the protonophore, carbonyl cyanide p-(trifluoromethoxy) phenylhydrazone (FCCP) was titrated until no further increase in respiration was detected. The ETS was then inhibited by adding rotenone (Complex I inhibitor) and antimycin-A (Complex III inhibitor). The remaining, primarily non-mitochondrial oxygen consumption (residual) was subtracted from the different respiratory states in further analyses. In intact cells, to determine the relative contribution of the different respiratory states, a control ratio was calculated as the ratio of maximal FCCP-stimulated respiration and state 4 respiration.
Experimental protocol for permeabilized cells
The next protocol was established to separate the respiratory capacities through Complex I and Complex II as achieved in conventional respirometric protocols. In addition, maximal phosphorylating and non-phosphorylating respiration were measured as stimulated by combined succinate plus NADH-related substrate supply. This substrate combination is required as a basis to reconstitute the citric acid cycle function in permeabilized cells or isolated mitochondria, with convergent Complex I and II electron input . Sequential additions were performed in a substrate, uncoupler, inhibitor titration (SUIT) protocol. Platelets were allowed to stabilize at routine respiration without exogenous substrates in MiR05, and were then permeabilized with digitonin in order to access the mitochondria with the different respiratory substrates and ADP. In a different set of experiments the optimal concentration of digitonin was set to 1 μg/1 × 106 platelets (data not shown). Respiration through Complex I, driven by NADH-related substrates, was evaluated by adding first malate (5 mM) and pyruvate (5 mM), then ADP (1 mM), and finally glutamate (5 mM) (CIOXPHOS, or state 3CI). Maximal OXPHOS capacity by convergent input through both Complex I and Complex II was obtained by sequentially adding 10 mM succinate (CI+IIOXPHOS, or state 3CI+II) after NADH-related substrates and ADP. State 4 (with CI and CII substrates present) was evaluated by adding oligomycin and maximal capacity of the ETS was obtained by titrating FCCP (CI+IIETS). Inhibition of Complex I by rotenone revealed the ETS capacity supported by succinate through Complex II alone (CIIETS). Finally, residual oxygen consumption was determined by addition of antimycin-A. In permeabilized cells, control ratios were calculated for both maximal capacity of OXPHOS and ETS by dividing the respective rate with state 4 respiration. After experiments, analyzed samples were stored at -80 °C.
Determination of platelet mtDNA content
The analysis of platelet mtDNA content was adapted from  with modifications. Frozen samples were thawed and diluted 500 times in a lysis buffer (10 mM TRIS-HCl, 1 mM EDTA, salmon sperm DNA 1 ng/μl, pH 8.0). 10 μl of this dilution was amplified in a 25 μl PCR reaction containing 1 × Power SYBR® Green PCR Master Mix using an ABI Prism 7000 real-time PCR machine (Applied Biosystems Inc., Foster City, CA, USA) and 100 nM of each primer (Eurofins MWG-operon, GmbH, Ebersberg, Germany). The primers targeted the human mitochondrial COX-1 gene (forward: CCC CTG CCA TAA CCC AAT ACC A, reverse: CCA GCA GCT AGG ACT GGG AGA GA). The threshold cycle (Ct) values were related to a standard curve using cloned PCR products (kindly provided by P. Schjerling University of Copenhagen, Denmark). Due to relatively high variation, samples were analyzed in pentaplicate.
Cytochrome c determination
Human cytochrome c (Cyt c) content was quantified using an immunoassay kit (DCTC0, Quantikine®, R&D systems, Abingdon, UK). Frozen samples where thawed and sonicated and subsequently processed according to the manufacturer's instructions.
Demographic and clinical characteristics of patients and controls
Patients (n= 18)
Controls (n= 18)
64 (50 to 73)
51 (38 to 60)
Source of sepsis:
- Soft tissue
46 (41 to 51)
24 (16 to 26)
Severe sepsis/septic shock
90-day outcome dead/alive
Clinical characteristics of patients at the time of blood sampling
Day of sample 1
Day of sample 2
SOFA (median (IQR))
10 (7 to 13)
9 (5 to 11)
7 (3 to 9)
Noradrenaline infusion rate (μg/kg/min)
0.19 ± 0.04
0.09 ± 0.04
0.01 ± 0.01
Maximum lactate (mmol/L)
3.5 ± 0.6
2.0 ± 0.3
1.3 ± 0.3
Average B-glucose level (mmol/L)
9.5 ± 0.4
8.6 ± 0.6
8.0 ± 0.4
Platelet count (x 109/L)
153 ± 24
146 ± 23
146 ± 22
203 ± 21
131 ± 24
57 ± 16
73 ± 51
30 ± 21
4 ± 2
Platelet transfusion (patients)
Mitochondrial respiration of intact platelets
In intact platelets, FCCP-titrated maximal respiration gradually increased in septic patients during the first week after admission to the ICU. The maximal respiration (pmol O2 x s-1 × 10-8 platelets) increased significantly from Day 1 to 2 to Day 6 to 7, 29% in plasma (20.6 ± 1.2 vs 26.7 ± 2.1) and 45% in PBS glucose (18.9 ± 1.4 vs 27.4 ± 2.2). Compared to controls the increase was 60% in plasma (16.7 ± 0.8 vs 26.7 ± 2.1) and 85% in PBS glucose (15 ± 0.8 vs 27.4 ± 2.2) at Day 6 to 7 (Figure 1A). State 4 respiration in PBS glucose was not different from controls and did not change significantly over the week. In contrast, state 4 respiration determined in the patients' own septic plasma was significantly higher compared to controls at Day 3 to 4 and Day 6 to 7 and also significantly higher compared to PBS glucose at Day 1 to 2 and Day 3 to 4 but not at Day 6 to 7 (Figure 1B). When adjusted for Cyt c content, state 4 respiration in plasma was significantly higher, compared to control, also at Day 1 to 2 (data not shown). The control ratio (FCCP-titrated maximal respiration/state 4 respiration) of mitochondria in septic plasma decreased over the first days, due to the increase in state 4 respiration, and was significantly lower than controls at Day 3 to 4 (Figure 1C).
Mitochondrial respiration of permeabilized platelets
Respiratory changes in platelet mitochondria in relation to clinical parameters and mortality
Quantification of platelet mtDNA and Cyt c content
In this study we demonstrate several alterations in platelet mitochondrial respiratory function during the course of the first week in patients admitted to the ICU due to severe sepsis or septic shock. First, plasma from septic patients induced an elevated state 4 respiration (uncoupling) resulting in a decreased control ratio (FCCP-titrated maximal respiration/state 4 respiration) which was not seen when plasma was removed and platelets were incubated in "clear" respiration media such as PBS or the mitochondrial respiration medium MiR05. Second, mitochondrial respiratory capacity increased gradually and extensively during the week which was paralleled by an increase in mitochondrial Cyt c content. Third, non-survivors had a significantly more elevated level of respiratory capacity at Day 6 to 7 compared to survivors.
Platelets incubated in their own septic plasma had a significantly elevated state 4 respiration at Day 3 to 4 and Day 6 to 7 compared to controls resulting in a decreased control ratio. Increased state 4 respiration and reduced control ratios have been demonstrated previously in sepsis. D'Avila et al. found mitochondrial uncoupling in brain homogenates in a 24 h cecal ligation and puncture model (CLP) model in mice . Also, plasma taken from septic patients at Day 1 and Day 7 induced increased state 4 respiration in peripheral blood mononuclear cells from healthy controls . State 4 respiration, that is, when oxidation of respiratory substrates is not coupled to ATP synthesis, is the result of "leak" of protons, slip of protons within the proton pumps and exchange of cations across the inner mitochondrial membrane. The formation of reactive oxygen species (ROS) could also contribute to some extent to oxygen consumption and in the case of whole and permeabilized cell analysis, also non-mitochondrial oxidative processes. However, both of these latter processes were removed from the respiratory rates in the present study by subtracting the low residual oxygen consumption following Complex III inhibition. The mitochondrial permeability transition (mPT) has been implicated in sepsis [22, 23] but cannot readily explain the elevated state 4 respiration in the present data. Activation of mPT leads to loss of mitochondrial matrix substrates as well as dissipation of the proton-motive force which uncouples as well as inhibits respiration , but no inhibition of the ETS was detected in the present investigation. Uncoupling proteins (UCPs) have been implicated in sepsis where UCP3 has been shown to be upregulated in muscle in a CLP model in rats and UCP2 deficient mice were protected from LPS-induced liver failure [25, 26]. Also, ROS production is increased in sepsis and a proton leak; ROS feedback loop has been suggested where ROS increase proton leak which in turn reduces ROS production via lowering of the proton-motive force [27, 28]. In the present study, no increase in state 4 respiration was found when plasma was removed and platelets were incubated in PBS glucose. This suggests presence of a soluble or a rapidly metabolized factor in septic plasma that can induce mitochondrial uncoupling either alone or as an activator of endogenous pathways such as uncoupling proteins. Whatever the cause of the uncoupling it remains to be elucidated if this stands for a true pathophysiological mechanism or constitutes a protective mechanism in regulating ROS production.
Concomitantly, we found that the respiratory capacity of the platelet mitochondria increased by 29 to 54% depending on experimental conditions and up to about 85% compared to controls. The temporal increase was seen both at the level of individual complexes as well as in integrated respiration of intact platelets and was significant already early in the disease process (Day 3 to 4). mtDNA copy number per platelet remained stable over the seven days investigated suggesting that the increase did not come from an increased number of organelles in the cell and is in accordance with a previous study . In contrast, we noted a 19% rise in Cyt c protein, used here as a marker of cellular content of mitochondrial proteins. The body copes with increasing demands of energy supply via mitochondrial biogenesis . Cytokines which are known to be elevated in sepsis have also been shown to activate regulators of mitochondrial biogenesis such as peroxisome profilerator-activated receptor γ coactivator -1α (PGC-1α) . Biogenesis has also been proposed to play an important part in the recovery following sepsis. In a murine model of Staphylococcus aureus sepsis, Haden et al. demonstrated an early fall (Day 1) in liver mtDNA copy number. Subsequently they noted an increase in transcription of nuclear respiratory factor (NFR)-1, NRF-2, mitochondrial transcription factor A (Tfam) and PGC-1α already at Day 2 after the induction of sepsis. At Day 3 mtDNA copy numbers were restored to normal values . Apart from increased number of organelles, biogenesis can also lead to increased density of respiratory complexes per organelle [31, 32] and reversible protein phosphorylation has been suggested to be a key mechanism in modulating the post-translational function of respiratory complexes . Some of the observed increase in respiratory capacity could be related to a high turnover of platelets in sepsis creating a more freshly produced pool of mitochondria being studied. The difference in respiratory capacity, if any, of newly produced platelets compared to the circulating pool is not known. However, we find it unlikely that such a difference may explain the pronounced increase in respiration rate, as much as 85%, found in the septic patients. Also, there was no correlation between platelet count or change in platelet count and respiratory capacity at any of the time points studied. Four patients received platelet transfusions on the day of sampling which could confound the results. However, excluding the patients' data completely or from specific days of transfusion did not influence the main findings or conclusions of the study (data not shown). The results from the present study support the hypothesis that in the recovery from sepsis with organ failure there is increasing metabolic demands that is met via a progressive rise in mitochondrial respiratory capacity. The temporal increase in Cyt c suggests that this process is mediated, at least in part, via a higher mitochondrial density of ETS-related proteins. At present the correlation between a given increase in ETS proteins and the resulting change in respiratory capacity is unknown.
Surprisingly, non-survivors at 90 days displayed significantly elevated levels of respiratory capacity compared to survivors at Day 6 to 7; both in absolute values as well as expressed as control ratios. This stands somewhat in contrast with recent findings that survival after severe sepsis was associated with early activation of mitochondrial biogenesis . Also, survivors from septic or cardiogenic shock showed an increase in mtDNA/nDNA ratio in blood cells compared to non-survivors  although this finding could have been caused by a variation of different leucocyte proportions . Tissue differences set aside, the findings of the present study represent the functional result of the various stimuli on mitochondria during the septic process in contrast to experiments using different markers of mitochondrial biogenesis where the relationship to functional outcome is hard to predict. We propose that a more severe septic insult or a more marked host response to the bacterial invasion leads to higher levels of cytokines and stimulants of mitochondrial biogenesis resulting in a more elevated respiratory capacity in non-survivors. Lending support to this is the recent study by Kellum et al. showing that 90-day mortality was higher in patients with severe sepsis that had the highest cytokine response when presenting at the emergency department .
In contrast to several other studies [35–37] we were unable to detect any functional inhibition of the respiratory complexes in the septic patients. These differences could be related to animal vs. human subjects, tissue specificity or different experimental conditions. In a high turnover cell type such as platelets it is also possible that an early initiation of the stimulatory process to increase respiration seen in the present study obscures an eventual early negative influence on mitochondrial respiration.
The limitations of the present study include the relatively small group sizes. Further, the generalizability of the present findings to other vital organ systems is at present not known.
To our knowledge this is the first study of temporal changes in mitochondrial respiratory function in intact, viable and permeabilized platelets of septic patients. Platelets are an easy accessible source of viable mitochondria and proved to be well suited for repeated sampling and analysis of respiration. The present data indicate the presence of a soluble plasma factor in the initial stage of sepsis inducing uncoupling of platelet mitochondria leading to a decreased control ratio but no inhibition of respiratory complexes. The mitochondrial uncoupling was paralleled by a gradual and pronounced increase in mitochondrial respiratory capacity. This probably reflects a compensatory mitochondrial biogenic response to severe sepsis or septic shock, that was most pronounced in non-survivors, likely correlating to the severity of the septic insult.
In the early phase of sepsis, intact platelets suspended in their own plasma (but not in other media) demonstrated an elevated basal non-phophorylating respiration (state 4) indicating a respiratory uncoupling mediated by a soluble factor in plasma.
Multiple parameters of platelet mitochondrial respiratory capacity gradually and substantially increased during the first week of sepsis.
Non-survivors at 90 days demonstrated more elevated respiratory capacities compared to survivors.
- APACHE II:
acute physiology and chronic health evaluation score
cecal ligation and puncture
- Cyt c cytochrome c:
carbonyl cyanide p-(trifluoromethoxy) phenylhydrazone
mitochondrial respiration media
multiple organ failure
mitochondrial permeability transition
nuclear respiratory factor
phosphate buffered saline
profilerator-activated receptor γ coactivator -1α
platelet rich plasma
reactive oxygen species
simplified acute physiology score
sequential organ failure assessment
substrate: uncoupler: inhibitor titration
We thank Eleonor Åsander and Anne Adolfsson for technical and administrative assistance and Jan Bonde, Anders Perner, Martin L. Olsson and Tadeusz Wieloch for support.
This work was supported by the Swedish Research Council (reference number 2008-2634), the Foundation of the National Board of Health and Welfare, Carl og Ellen Hertz' legat til Dansk læge- og naturvidenskab, and the Lippman foundation.
- Mayr VD, Dunser MW, Greil V, Jochberger S, Luckner G, Ulmer H, Friesenecker BE, Takala J, Hasibeder WR: Causes of death and determinants of outcome in critically ill patients. Critical Care 2006, 10: R154. 10.1186/cc5086PubMed CentralView ArticlePubMedGoogle Scholar
- 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. Critical Care Medicine 1999, 27: 1230-1251. 10.1097/00003246-199907000-00002View ArticlePubMedGoogle Scholar
- Exline MC, Crouser ED: Mitochondrial mechanisms of sepsis-induced organ failure. Front Biosci 2008, 13: 5030-5041.PubMed CentralPubMedGoogle Scholar
- Porta F, Takala J, Weikert C, Bracht H, Kolarova A, Lauterburg BH, Borotto E, Jakob SM: Effects of prolonged endotoxemia on liver, skeletal muscle and kidney mitochondrial function. Critical Care 2006, 10: R118. 10.1186/cc5013PubMed CentralView ArticlePubMedGoogle Scholar
- Haden DW, Suliman HB, Carraway MS, Welty-Wolf KE, Ali AS, Shitara H, Yonekawa H, Piantadosi CA: Mitochondrial biogenesis restores oxidative metabolism during Staphylococcus aureus sepsis. American Journal of Respiratory and Critical Care Medicine 2007, 176: 768-777. 10.1164/rccm.200701-161OCPubMed CentralView ArticlePubMedGoogle Scholar
- Carre JE, Orban JC, Re L, Felsmann K, Iffert W, Bauer M, Suliman HB, Piantadosi CA, Mayhew TM, Breen P, Stotz M, Singer M: Survival in critical illness is associated with early activation of mitochondrial biogenesis. American Journal of Respiratory and Critical Care Medicine 2010, 182: 745-751. 10.1164/rccm.201003-0326OCPubMed CentralView ArticlePubMedGoogle Scholar
- Richter C, Park JW, Ames BN: Normal oxidative damage to mitochondrial and nuclear DNA is extensive. Proc Natl Acad Sci USA 1988, 85: 6465-6467. 10.1073/pnas.85.17.6465PubMed CentralView ArticlePubMedGoogle Scholar
- Pyle A, Burn DJ, Gordon C, Swan C, Chinnery PF, Baudouin SV: Fall in circulating mononuclear cell mitochondrial DNA content in human sepsis. Intensive Care Medicine 2010, 36: 956-962. 10.1007/s00134-010-1823-7PubMed CentralView ArticlePubMedGoogle Scholar
- Cote HC, Day AG, Heyland DK: Longitudinal increases in mitochondrial DNA levels in blood cells are associated with survival in critically ill patients. Critical Care 2007, 11: R88. 10.1186/cc6096PubMed CentralView ArticlePubMedGoogle Scholar
- Shuster RC, Rubenstein AJ, Wallace DC: Mitochondrial DNA in anucleate human blood cells. Biochem Biophys Res Commun 1988, 155: 1360-1365. 10.1016/S0006-291X(88)81291-9View ArticlePubMedGoogle Scholar
- Clark SR, Ma AC, Tavener SA, McDonald B, Goodarzi Z, Kelly MM, Patel KD, Chakrabarti S, McAvoy E, Sinclair GD, Keys EM, Allen-Vercoe E, Devinney R, Doig CJ, Green FH, Kubes P: Platelet TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood. Nat Med 2007, 13: 463-469. 10.1038/nm1565View ArticlePubMedGoogle Scholar
- Merlo Pich M, Bovina C, Formiggini G, Cometti GG, Ghelli A, Parenti Castelli G, Genova ML, Marchetti M, Semeraro S, Lenaz G: Inhibitor sensitivity of respiratory complex I in human platelets: a possible biomarker of ageing. FEBS Lett 1996, 380: 176-178. 10.1016/0014-5793(96)00037-3View ArticlePubMedGoogle Scholar
- Xu J, Shi C, Li Q, Wu J, Forster EL, Yew DT: Mitochondrial dysfunction in platelets and hippocampi of senescence-accelerated mice. J Bioenerg Biomembr 2007, 39: 195-202. 10.1007/s10863-007-9077-yView ArticlePubMedGoogle Scholar
- Kunz D, Luley C, Fritz S, Bohnensack R, Winkler K, Kunz WS, Wallesch CW: Oxygraphic evaluation of mitochondrial function in digitonin-permeabilized mononuclear cells and cultured skin fibroblasts of patients with chronic progressive external ophthalmoplegia. Biochemical and Molecular Medicine 1995, 54: 105-111. 10.1006/bmme.1995.1015View ArticlePubMedGoogle Scholar
- Sjövall F, Morota S, Hansson MJ, Friberg H, Gnaiger E, Elmer E: Sepsis induces platelet mitochondrial uncoupling and a gradual increase in respiratory capacity that is negatively associated with clinical outcome. Crit Care 2010, 14: R214.PubMed CentralView ArticlePubMedGoogle Scholar
- Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA, Schein RM, Sibbald WJ: Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest 1992, 101: 1644-1655. 10.1378/chest.101.6.1644View ArticlePubMedGoogle Scholar
- Gnaiger E, Kuznetsov AV, Schneeberger S, Seiler R, Brandacher G, Steurer W, Margreiter R: Mitochondria in the cold. In Life in the Cold. Edited by: Heldmaier G, Klingenspor M. Heidelberg, Berlin, New York: Springer; 2000:431-442.View ArticleGoogle Scholar
- Gnaiger E: Capacity of oxidative phosphorylation in human skeletal muscle: new perspectives of mitochondrial physiology. Int J Biochem Cell Biol 2009, 41: 1837-1845. 10.1016/j.biocel.2009.03.013View ArticlePubMedGoogle Scholar
- Boushel R, Gnaiger E, Schjerling P, Skovbro M, Kraunsoe R, Dela F: Patients with type 2 diabetes have normal mitochondrial function in skeletal muscle. Diabetologia 2007, 50: 790-796. 10.1007/s00125-007-0594-3PubMed CentralView ArticlePubMedGoogle Scholar
- d'Avila JC, Santiago AP, Amancio RT, Galina A, Oliveira MF, Bozza FA: Sepsis induces brain mitochondrial dysfunction. Critical Care Medicine 2008, 36: 1925-1932.View ArticlePubMedGoogle Scholar
- Belikova I, Lukaszewicz AC, Faivre V, Damoisel C, Singer M, Payen D: Oxygen consumption of human peripheral blood mononuclear cells in severe human sepsis. Critical Care Medicine 2007, 35: 2702-2708. 10.1097/01.CCM.0000295593.25106.C4View ArticlePubMedGoogle Scholar
- 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. Journal of the American College of Cardiology 2006, 48: 377-385. 10.1016/j.jacc.2006.02.069View ArticlePubMedGoogle Scholar
- Crouser ED, Julian MW, Huff JE, Joshi MS, Bauer JA, Gadd ME, Wewers MD, Pfeiffer DR: Abnormal permeability of inner and outer mitochondrial membranes contributes independently to mitochondrial dysfunction in the liver during acute endotoxemia. Critical Care Medicine 2004, 32: 478-488. 10.1097/01.CCM.0000109449.99160.81View ArticlePubMedGoogle Scholar
- Hansson MJ, Morota S, Teilum M, Mattiasson G, Uchino H, Elmer E: Increased potassium conductance of brain mitochondria induces resistance to permeability transition by enhancing matrix volume. The Journal of Biological Chemistry 2010, 285: 741-750. 10.1074/jbc.M109.017731PubMed CentralView ArticlePubMedGoogle Scholar
- Sun X, Wray C, Tian X, Hasselgren PO, Lu J: Expression of uncoupling protein 3 is upregulated in skeletal muscle during sepsis. Am J Physiol Endocrinol Metab 2003, 285: E512-520.View ArticlePubMedGoogle Scholar
- Le Minh K, Kuhla A, Abshagen K, Minor T, Stegemann J, Ibrahim S, Eipel C, Vollmar B: Uncoupling protein-2 deficiency provides protection in a murine model of endotoxemic acute liver failure. Critical Care Medicine 2009, 37: 215-222. 10.1097/CCM.0b013e31819260aeView ArticlePubMedGoogle Scholar
- Brookes PS: Mitochondrial H(+) leak and ROS generation: an odd couple. Free Radic Biol Med 2005, 38: 12-23. 10.1016/j.freeradbiomed.2004.10.016View ArticlePubMedGoogle Scholar
- Echtay KS: Mitochondrial uncoupling proteins--what is their physiological role? Free Radic Biol Med 2007, 43: 1351-1371. 10.1016/j.freeradbiomed.2007.08.011View ArticlePubMedGoogle Scholar
- Freyssenet D, Berthon P, Denis C: Mitochondrial biogenesis in skeletal muscle in response to endurance exercises. Arch Physiol Biochem 1996, 104: 129-141. 10.1076/apab.126.96.36.19978View ArticlePubMedGoogle Scholar
- Puigserver P, Rhee J, Lin J, Wu Z, Yoon JC, Zhang CY, Krauss S, Mootha VK, Lowell BB, Spiegelman BM: Cytokine stimulation of energy expenditure through p38 MAP kinase activation of PPARgamma coactivator-1. Mol Cell 2001, 8: 971-982. 10.1016/S1097-2765(01)00390-2View ArticlePubMedGoogle Scholar
- Nisoli E, Carruba MO: Nitric oxide and mitochondrial biogenesis. J Cell Sci 2006, 119: 2855-2862. 10.1242/jcs.03062View ArticlePubMedGoogle Scholar
- Kelly DP, Scarpulla RC: Transcriptional regulatory circuits controlling mitochondrial biogenesis and function. Genes Dev 2004, 18: 357-368. 10.1101/gad.1177604View ArticlePubMedGoogle Scholar
- Pagliarini DJ, Dixon JE: Mitochondrial modulation: reversible phosphorylation takes center stage? Trends Biochem Sci 2006, 31: 26-34. 10.1016/j.tibs.2005.11.005View ArticlePubMedGoogle Scholar
- Kellum JA, Kong L, Fink MP, Weissfeld LA, Yealy DM, Pinsky MR, Fine J, Krichevsky A, Delude RL, Angus DC: Understanding the inflammatory cytokine response in pneumonia and sepsis: results of the Genetic and Inflammatory Markers of Sepsis (GenIMS) Study. Arch Intern Med 2007, 167: 1655-1663. 10.1001/archinte.167.15.1655PubMed CentralView ArticlePubMedGoogle Scholar
- 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: 219-223. 10.1016/S0140-6736(02)09459-XView ArticlePubMedGoogle Scholar
- Crouser ED, Julian MW, Blaho DV, Pfeiffer DR: Endotoxin-induced mitochondrial damage correlates with impaired respiratory activity. Critical Care Medicine 2002, 30: 276-284. 10.1097/00003246-200202000-00002View ArticlePubMedGoogle Scholar
- 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. American Journal Of Physiology 2004, 286: R491-497.PubMedGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (<url>http://creativecommons.org/licenses/by/2.0</url>), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.