Plasma Cytochrome c
Cytochrome c is a 14-kDa mitochondrial protein that plays a key role in oxidative phosphorylation enabling electron transfer from complex III to complex IV of the respiratory chain. Cytochrome c can be released to the bloodstream under various pathological conditions including injury by ischemia and reperfusion.
We have shown in rat models of cardiac arrest release of cytochrome c to the bloodstream attaining plasma levels inversely proportional to myocardial function and survival.1,2 Likewise, in studies investigating pharmacological interventions to protect mitochondria from reperfusion injury, better post-resuscitation myocardial function is accompanied by proportionally lower plasma levels of cytochrome c.3,4
In humans, plasma levels of cytochrome c are lower after cardiac arrest and after septic shock in those who survive the event.5,6 In addition, plasma levels of cytochrome c in trauma victims correlate inversely with the survival probability estimated by Trauma Score–Injury Severity Score (TRISS).7
At the Resuscitation Institute, we have developed various assays to measure plasma cytochrome c demonstrating the highest sensitivity with the broadest dynamic range using an electrochemiluminescence immunoassay.7,8
- Radhakrishnan J, Wang S, Ayoub IM, Kolarova JD, Levine RF, Gazmuri RJ. Circulating levels of cytochrome c after resuscitation from cardiac arrest: a marker of mitochondrial injury and predictor of survival. Am J Physiol Heart Circ Physiol. 2007 Feb;292(2):H767-75.
- Radhakrishnan J, Ayoub IM, Gazmuri RJ. Activation of caspase-3 may not contribute to postresuscitation myocardial dysfunction. Am J Physiol Heart Circ Physiol. 2009 Apr;296(4):H1164-74.
- Radhakrishnan J, Kolarova JD, Ayoub IM, Gazmuri RJ. AVE4454B–a novel sodium-hydrogen exchanger isoform-1 inhibitor–compared less effective than cariporide for resuscitation from cardiac arrest. Transl Res. 2011 Feb;157(2):71-80.
- Radhakrishnan J, Upadhyaya MP, Ng M, Edelheit A, Moy HM, Ayoub IM, Gazmuri RJ. Erythropoietin facilitates resuscitation from ventricular fibrillation by signaling protection of mitochondrial bioenergetic function in rats. Am J Transl Res. 2013 Apr 19;5(3):316-26.
- Andersen LW, Liu X, Montissol S, Holmberg MJ, Sulmonte C, Balkema JL, Cocchi MN, Gazmuri RJ, Berg KM, Chase M, Donnino MW. Cytochrome C in Patients with Septic Shock. Shock. 2016 May;45(5):512-7.
- Donnino MW, Liu X, Andersen LW, Rittenberger JC, Abella BS, Gaieski DF, Ornato JP, Gazmuri RJ, Grossestreuer AV, Cocchi MN, Abbate A, Uber A, Clore J, Peberdy MA, Callaway CW; National Post Arrest Research Consortium (NPARC) Investigators. Characterization of mitochondrial injury after cardiac arrest (COMICA). Resuscitation. 2017 Apr;113:56-62.
- Radhakrishnan J, Origenes R, Littlejohn G, Nikolich S, Choi E, Smite S, Lamoureux L, Baetiong A, Shah M, Gazmuri RJ. Plasma Cytochrome c Detection Using a Highly Sensitive Electrochemiluminescence Enzyme-Linked Immunosorbent Assay. Biomark Insights. 2017 Dec 13;12:1177271917746972.
- Donnino MW, Mortensen SJ, Andersen LW, Chase M, Berg KM, Balkema J, Radhakrishnan J, Gazmuri RJ, Liu X, Cocchi MN. Ubiquinol (reduced Coenzyme Q10) in patients with severe sepsis or septic shock: a randomized, double-blind, placebo-controlled, pilot trial. Crit Care. 2015 Jul 1;19(1):275.
We plan to further develop our plasma cytochrome c assay to assess interventions targeting mitochondria in preclinical and in clinical studies. Stay tuned…