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

¹Department of Transplant Surgery, D. Swarovski Research Laboratory, University Hospital Innsbruck, A-6020 Innsbruck, Austria; ²Laboratory of Bioenergetics, Joseph Fourier University, Grenoble Cedex 9; and ³Techniques de l'Imagerie de la Modelisation et de la Cognition Laboratory, UMR5525 Centre National de la Recherche Scientifique, Institute Albert Bonniot, Grenoble 38706, France

Submitted 21 July 2003 ; accepted in final form 19 December 2003

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.

respiration; heart preservation; complex I injury; permeabilized myocardial fibers

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