Coenzyme Q10 deficiency in septic shock patients

Donnino and colleagues provide new insights into the field of oxidative stress and mitochondrial dysfunction during septic shock. These authors suggest a coenzyme Q10 (CoQ10) deficiency in patients with septic shock. Larger prospective observational trials measuring CoQ10 in patients with septic shock are required to confirm the possibility of CoQ10 depletion. This study is a new step toward a study testing CoQ10 as a potential therapeutic agent for patients with septic shock.

In the previous issue of Critical Care, Donnino and colleagues [1] suggest a coenzyme Q 10 (CoQ 10 ) defi ciency in patients with septic shock. Th is study provides new insights into the fi eld of oxidative stress and mito chondrial dysfunction during septic shock. Th ough extensively studied, the pathophysiology of sepsis-associated multiorgan failure (MOF) remains unknown. Sepsis is characterized by a systemic dysregulated infl ammatory response and oxidative stress. One postulated mechanism is a set of changes in mitochondrial function with an inhibition or a dysfunction of the mitochondrial respiratory chain and a decrease of oxygen use [2]. A large body of evidence supports a key role of excessive production of reactive oxygen species in mitochondrial dysfunction and cellular injury during the various phases of sepsis (earlyand late-phase MOF) [3,4]. Understanding the precise eff ect of sepsis on the mitochondrial function and the involvement of mitochondria in the development of MOF is fundamental.
CoQ 10 , also known as ubiquinone, plays a crucial role in the mitochondrial respiratory chain for ATP production. CoQ 10 is a lipophilic mobile electron carrier that is located in the inner mitochondrial membrane. CoQ 10 receives electrons from complex I (NADH dehydro genase) and complex II (succinate dehydrogenase) (reduction of ubiquinone to ubiquinol). Complex III (coenzyme Q-cytochrome c reductase) accepts electrons from ubiqui nol and passes them to cytochrome c. CoQ 10 has been reported to have the ability to act as an eff ective antioxidant. Ubiquinone prevents peroxidation damage to cell membranes, regenerates α-tocopherol, and maintains thiol levels. CoQ 10 is also a cofactor for uncoupling proteins. Finally, CoQ 10 plays a role in the control of mitochondrial transition pore opening, which is involved in apoptosis.
Several studies suggest an important role of CoQ 10 defi ciency in neurodegenerative conditions such as Parkin son disease, Friedreich ataxia, and Huntington chorea and a benefi t of oral supplementation [5]. In addition, CoQ 10 defi ciency could play a role in the pathogenesis of heart failure. Recently, McMurray and colleagues [6] reported that a low serum CoQ 10 concentration was associated with worse outcomes in heart failure. It is important to note that, in that study, CoQ 10 was a marker of more advanced disease but that low plasma coenzyme CoQ 10 was not an independent predictor of prognosis.
So if there is a defi cit in CoQ 10 during sepsis, the drug could be used in the prevention and treatment of sepsisassociated MOF to boost mitochondrial function and to mitigate cellular damage caused by oxidative stress. Until now, only animal models have been used to test the impact of CoQ 10 on the consequences of sepsis. Injection of CoQ 10 into the rostral ventrolateral medulla (medullary origin of sympathetic vasomotor tone) of rats diminished mortality and lipopolysaccharide-induced hypotension during exposure to lipopolysaccharide [7]. Lowes and colleagues [8] reported that MitoQ, an antioxidant this is selectively targeted to mitochondria and that comprises the lipophilic triphenylphosphonium cation covalently bound to ubiquinol, was able to limit oxidative stress, maintain the mitochondrial membrane potential, and prevent mitochondrial damage (endothelial cell model of sepsis) and acute liver and renal dysfunction (rat model of sepsis). In rat and mouse models of sepsis induced by endotoxin injected intra peritoneally, Supinski and colleagues [9] demonstrated that MitoQ prevented endotoxin-induced reductions in cardiac pressure-generating capacity, systolic Abstract Donnino and colleagues provide new insights into the fi eld of oxidative stress and mitochondrial dysfunction during septic shock. These authors suggest a coenzyme Q 10 (CoQ 10 ) defi ciency in patients with septic shock. Larger prospective observational trials measuring CoQ 10 in patients with septic shock are required to confi rm the possibility of CoQ 10 depletion. This study is a new step toward a study testing CoQ 10 as a potential therapeutic agent for patients with septic shock. pressure-diastolic relationship, and mitochondrial respiration rates. Th ese authors found that MitoQ prevented the endotoxin-induced increase of cardiac levels of active caspases 9 and 3.
In this context, Donnino and colleagues [1] provide useful new information. Th ey report that CoQ 10 levels of patients with septic shock are signifi cantly lower than those of healthy controls. Th is result is interesting because it is the fi rst report of low CoQ 10 levels in patients with septic shock. A major point to be considered in the interpretation of these low CoQ 10 levels is the set of changes in its major carriers, the low-and highdensity lipoproteins, because the levels of these carriers can be aff ected by sepsis. Th e main limitation of this study is that it is a post hoc analysis of a prospective randomized trial of simvastatin versus placebo in patients with septic shock. As several studies have reported that patients treated with statins showed signifi cant decreases in plasma/serum CoQ 10 [10], it could be argued that the observed low CoQ 10 levels are due to the simvastatin group. But there was no signifi cant diff erence in change in mean CoQ 10 between randomization groups. However, as men tioned by the authors, the sample size for this study is small and larger prospective observational trials measur ing CoQ 10 in patients with septic shock are required. But do these low CoQ 10 levels imply CoQ 10 supplementation in patients with sepsis? While we share the enthusiasm for CoQ 10 supplementation and mitochondria-targeted CoQ 10 as putative therapies in sepsis, low CoQ 10 levels could be associated with greater disease severity without playing an important mechanistic role in the patho physiology of sepsis. Th is question can be defi nitively answered only by appropriately designed clinical trials testing the therapeutic effi cacy of CoQ 10 supplementation or mitochondria-targeted CoQ 10 .
In conclusion, Donnino and colleagues [1] provide original data suggesting a CoQ 10 defi ciency in patients with septic shock. Th is is an exciting hypothesis in the fi eld of oxidative stress and mitochondrial dysfunction during septic shock. Th is study is a new step toward a study testing CoQ 10 as a potential therapeutic agent for patients with septic shock.