Mitochondrial defects and heterogeneous cytochrome c release after cardiac cold ischemia and reperfusion

Andrey V. Kuznetsov, Stefan Schneeberger, Rüdiger Seiler, Gerald Brandacher, Walter Mark, Wolfgang Steurer, Valdur Saks, Yves Usson, Raimund Margreiter, Erich Gnaiger

Research output: Contribution to journalArticle

Abstract

Mitochondria play a critical role in myocardial cold ischemia-reperfusion (CIR) and induction of apoptosis. The nature and extent of mitochondrial defects and cytochrome c (Cyt c) release were determined by high-resolution respirometry in permeabilized myocardial fibers. CIR in a rat heart transplant model resulted in variable contractile performance, correlating with the decline of ADP-stimulated respiration. Respiration with succinate or N,N,N′,N′-tetramethyl-p-phenylenediamine dihydrochloride (substrates for complexes II and IV) was partially restored by added Cyt c, indicating Cyt c release. In contrast, NADH-linked respiration (glutamate+malate) was not stimulated by Cyt c, owing to a specific defect of complex I. CIR but not cold ischemia alone resulted in the loss of NADH-linked respiratory capacity, uncoupling of oxidative phosphorylation and Cyt c release. Mitochondria depleted of Cyt c by controlled hypoosmotic shock provided a kinetic model of homogenous Cyt c depletion. Comparison to Cyt c control of respiration in CIR-injured myocardial fibers indicated heterogeneity of Cyt c release. The complex I defect and uncoupling correlated with heterogeneous Cyt c release, the extent of which increased with loss of cardiac performance. These results demonstrate a complex pattern of multiple mitochondrial damage as determinants of CIR injury of the heart.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume286
Issue number5 55-5
DOIs
StatePublished - May 2004
Externally publishedYes

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Keywords

  • Complex I injury
  • Heart preservation
  • Permeabilized myocardial fibers
  • Respiration

ASJC Scopus subject areas

  • Physiology

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