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

1 Department of Transplant Surgery, D. Swarovski Research Laboratory, University Hospital Innsbruck, A-6020 Innsbruck, Austria; 2 Laboratory of Bioenergetics, Joseph Fourier University, Grenoble Cedex 9; and 3 Techniques de l'Imagerie de la Modelisation et de la Cognition Laboratory, UMR5525 Ce...

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Published in:American journal of physiology. Heart and circulatory physiology 2004-05, Vol.286 (5), p.H1633-H1641
Main Authors: Kuznetsov, Andrey V, Schneeberger, Stefan, Seiler, Rudiger, Brandacher, Gerald, Mark, Walter, Steurer, Wolfgang, Saks, Valdur, Usson, Yves, Margreiter, Raimund, Gnaiger, Erich
Format: Article
Language:English
Subjects:
Animals
Bioengineering
Cryopreservation
Cytochromes c
Cytochromes c - metabolism
Electron Transport Complex I
Electron Transport Complex I - metabolism
Heart
Heart - physiopathology
Imaging
In Vitro Techniques
Kinetics
Life Sciences
Male
Mitochondria, Heart
Mitochondria, Heart - metabolism
Myocardial Contraction
Myocardial Ischemia
Myocardial Ischemia - metabolism
Myocardial Ischemia - physiopathology
Myocardial Reperfusion Injury
Myocardial Reperfusion Injury - metabolism
Myocardial Reperfusion Injury - physiopathology
Oxygen Consumption
Rats
Rats, Inbred Lew
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Summary:1 Department of Transplant Surgery, D. Swarovski Research Laboratory, University Hospital Innsbruck, A-6020 Innsbruck, Austria; 2 Laboratory of Bioenergetics, Joseph Fourier University, Grenoble Cedex 9; and 3 Techniques 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 Address for reprint requests and other correspondence: E. Gnaiger, Dept. of Transplant Surgery, D. Swarovski Research Laboratory, Univ. Hospital Innsbruck, Innrain 66/6, A-6020 Innsbruck, Austria (E-mail: erich.gnaiger{at}uibk.ac.at ).
ISSN:0363-6135
1522-1539
DOI:10.1152/ajpheart.00701.2003