Mitochondrial resuscitation with exogenous cytochrome c in the septic heart.

OBJECTIVE

Mitochondrial dysfunction may play a role in the pathogenesis of sepsis-induced organ dysfunction. Respiratory-chain deficiencies that occur in sepsis, however, have never been shown to cause organ failure or to be reversible. Cytochrome oxidase uses electrons donated by its substrate, cytochrome c, to reduce oxygen to H2O. In the septic heart, cytochrome oxidase is competitively inhibited. We hypothesized that cytochrome oxidase inhibition coupled with reduced substrate availability is a reversible cause of sepsis-associated myocardial depression.

DESIGN

Prospective observational study aimed to overcome myocardial cytochrome oxidase inhibition with excess cytochrome c and improve cardiac function.

SETTING

University hospital-based laboratory.

SUBJECTS

Seventy-five C57Bl6 male mice.

INTERVENTIONS

Mice underwent cecal ligation and double puncture, sham operation, or no operation. Exogenous cytochrome c or an equal volume of saline was intravenously injected at the 24-hr time point. All animals were evaluated 30 mins after injection.

MEASUREMENTS AND MAIN RESULTS

Exogenous cytochrome c readily repleted cardiac mitochondria with supranormal levels of substrate (>1.6 times baseline), restored heme c content, and increased cytochrome oxidase kinetic activity. This increased left ventricular pressure and increased pressure development during isovolumic contraction (dP/dtmax) and relaxation (dP/dtmin) by >45% compared with saline injection.

CONCLUSION

Impaired oxidative phosphorylation is a cause of sepsis-associated myocardial depression, and mitochondrial resuscitation with exogenous cytochrome c overcomes cytochrome oxidase inhibition and improves cardiac function.