title: Mitochondrial resuscitation with exogenous cytochrome c in the septic heart.
abstract: 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.
  
  
  METHODS
  Prospective observational study aimed to overcome myocardial cytochrome oxidase inhibition with excess cytochrome c and improve cardiac function.
  
  
  METHODS
  University hospital-based laboratory.
  
  
  METHODS
  Seventy-five C57Bl6 male mice.
  
  
  METHODS
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, The Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Piel
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Gruber
authors.forename: Carla J
authors.initials: CJ
authors.lastname: Weinheimer
authors.forename: Michael R
authors.initials: MR
authors.lastname: Courtois
authors.forename: Charles M
authors.initials: CM
authors.lastname: Robertson
authors.forename: Craig M
authors.initials: CM
authors.lastname: Coopersmith
authors.forename: Clifford S
authors.initials: CS
authors.lastname: Deutschman
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Levy
mesh_terms: D000818:Animals; D045304:Cytochromes c / Q000494:pharmacology*; D003576:Electron Transport Complex IV / Q000037:antagonists & inhibitors; D006418:Heme / Q000031:analogs & derivatives / Q000032:analysis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008929:Mitochondria, Heart / Q000737:chemistry / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D010085:Oxidative Phosphorylation; D011446:Prospective Studies; D018805:Sepsis / Q000188:drug therapy / Q000503:physiopathology*
chemical_list: C031690:heme C; D006418:Heme; D045304:Cytochromes c; D003576:Electron Transport Complex IV