Coenzyme Q10 deficiency in septic shock patients
Critical Care volume 15, Article number: 194 (2011)
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  suggest a coenzyme Q10 (CoQ10) deficiency in patients with septic shock. This study provides new insights into the field of oxidative stress and mitochondrial dysfunction during septic shock. Though extensively studied, the pathophysiology of sepsis-associated multi-organ failure (MOF) remains unknown. Sepsis is characterized by a systemic dysregulated inflammatory 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 . 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 (early-and late-phase MOF) [3, 4]. Understanding the precise effect of sepsis on the mitochondrial function and the involvement of mitochondria in the development of MOF is fundamental.
CoQ10, also known as ubiquinone, plays a crucial role in the mitochondrial respiratory chain for ATP production. CoQ10 is a lipophilic mobile electron carrier that is located in the inner mitochondrial membrane. CoQ10 receives electrons from complex I (NADH dehydrogenase) and complex II (succinate dehydrogenase) (reduction of ubiquinone to ubiquinol). Complex III (coenzyme Q-cytochrome c reductase) accepts electrons from ubiquinol and passes them to cytochrome c. CoQ10 has been reported to have the ability to act as an effective antioxidant. Ubiquinone prevents peroxidation damage to cell membranes, regenerates α-tocopherol, and maintains thiol levels. CoQ10 is also a cofactor for uncoupling proteins. Finally, CoQ10 plays a role in the control of mitochondrial transition pore opening, which is involved in apoptosis.
Several studies suggest an important role of CoQ10 deficiency in neurodegenerative conditions such as Parkinson disease, Friedreich ataxia, and Huntington chorea and a benefit of oral supplementation . In addition, CoQ10 deficiency could play a role in the pathogenesis of heart failure. Recently, McMurray and colleagues  reported that a low serum CoQ10 concentration was associated with worse outcomes in heart failure. It is important to note that, in that study, CoQ10 was a marker of more advanced disease but that low plasma coenzyme CoQ10 was not an independent predictor of prognosis.
So if there is a deficit in CoQ10 during sepsis, the drug could be used in the prevention and treatment of sepsis-associated 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 CoQ10 on the consequences of sepsis. Injection of CoQ10 into the rostral ventrolateral medulla (medullary origin of sympathetic vasomotor tone) of rats diminished mortality and lipopolysaccharide-induced hypotension during exposure to lipopolysaccharide . Lowes and colleagues  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 intraperitoneally, Supinski and colleagues  demonstrated that MitoQ prevented endotoxin-induced reductions in cardiac pressure-generating capacity, systolic pressure-diastolic relationship, and mitochondrial respiration rates. These authors found that MitoQ prevented the endotoxin-induced increase of cardiac levels of active caspases 9 and 3.
In this context, Donnino and colleagues  provide useful new information. They report that CoQ10 levels of patients with septic shock are significantly lower than those of healthy controls. This result is interesting because it is the first report of low CoQ10 levels in patients with septic shock. A major point to be considered in the interpretation of these low CoQ10 levels is the set of changes in its major carriers, the low- and high-density lipoproteins, because the levels of these carriers can be affected by sepsis. The 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 significant decreases in plasma/serum CoQ10, it could be argued that the observed low CoQ10 levels are due to the simvastatin group. But there was no significant difference in change in mean CoQ10 between randomization groups. However, as mentioned by the authors, the sample size for this study is small and larger prospective observational trials measuring CoQ10 in patients with septic shock are required. But do these low CoQ10 levels imply CoQ10 supplementation in patients with sepsis? While we share the enthusiasm for CoQ10 supplementation and mitochondria-targeted CoQ10 as putative therapies in sepsis, low CoQ10 levels could be associated with greater disease severity without playing an important mechanistic role in the pathophysiology of sepsis. This question can be definitively answered only by appropriately designed clinical trials testing the therapeutic efficacy of CoQ10 supplementation or mitochondria-targeted CoQ10.
In conclusion, Donnino and colleagues  provide original data suggesting a CoQ10 deficiency in patients with septic shock. This is an exciting hypothesis in the field of oxidative stress and mitochondrial dysfunction during septic shock. This study is a new step toward a study testing CoQ10 as a potential therapeutic agent for patients with septic shock.
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The authors declare that they have no competing interests.