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Cardiovascular Research Advance Access [Accepted Manuscript] published online on June 3, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp181
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Published by Oxford University Press on behalf of the European Society of Cardiology 2009.

Mitochondrial OPA1, Apoptosis and Heart Failure

Le Chen, M.D., Ph.D.1, Qizhi Gong, Ph.D.2, James P. Stice1 and A.A. Knowlton, M.D.1,3,4

1 Molecular and Cellular Cardiology, Department of Medicine
2 Department of Cell Biology and Human Anatomy, and
3 Department of Pharmacology, University of California, Davis, Davis CA and the
4 Northern California VA, Sacramento, CA

Address for Correspondence: A.A. Knowlton, M.D. Molecular & Cellular Cardiology, University of California, Davis, One Shields Avenue, Davis, CA 95616. Tel. - 530-752-5461; Fax - 530-754-7167; E-mail- aaknowlton{at}ucdavis.edu

Aims: Mitochondrial fusion and fission are essential processes for preservation of normal mitochondrial function. We hypothesized that fusion proteins would be decreased in heart failure (HF), as the mitochondria in HF have been reported to be small and dysfunctional.

Methods and Results: Expression of optic atrophy 1 (OPA1), a mitochondrial fusion protein, was decreased in both human and rat HF, as observed by western blotting. OPA1 is important for maintaining normal cristae structure and function, for preserving the inner membrane structure and for protecting cells from apoptosis. Confocal and electron microscopy studies demonstrated that the mitochondria in the failing hearts were small and fragmented, consistent with decreased fusion. OPA1 mRNA levels did not differ between failing and normal hearts, suggesting post-transcriptional control. Simulated ischemia in the cardiac myogenic cell line H9c2 cells reduced OPA protein levels. Reduction of OPA1 expression with shRNA resulted in increased apoptosis and fragmentation of the mitochondria. Overexpression of OPA1 increased mitochondrial tubularity, but did not protect against simulated ischemia-induced apoptosis. Cytochrome c release from the mitochondria was increased with both reduction in OPA1 and with overexpression of OPA1.

Conclusions: This is the first report, to our knowledge, of changes in mitochondrial fusion/fission proteins in cardiovascular disease. These changes have implications for mitochondrial function and apoptosis, contributing to the cell loss which is part of the downward progression of the failing heart.

KEYWORDS apoptosis; heart failure; ischemia; mitochondria; fission; fusion

Time for primary review: 33 Days


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