Circulation Research. 2003;92:186-194
Published online before print December 12, 2002, doi: 10.1161/01.RES.0000051861.21316.E9
Published online before print December 12, 2002, doi: 10.1161/01.RES.0000051861.21316.E9
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© 2003 American Heart Association, Inc.
Cellular Biology |
Mechanistically Distinct Steps in the Mitochondrial Death Pathway Triggered by Oxidative Stress in Cardiac Myocytes
From the Institute of Molecular Cardiobiology, The Johns Hopkins University, Baltimore, Md.
Correspondence to Eduardo Marbán, MD, PhD, FACC, Institute of Molecular Cardiobiology, The Johns Hopkins University, 720 Rutland Ave, 844 Ross Bldg, Baltimore, MD 21205. E-mail marban{at}jhmi.edu
Oxidative stress plays an important role in the pathogenesis of cardiovascular diseases. In the present study, we characterize three distinct phases of the H2O2-induced response, which leads to loss of mitochondrial membrane potential (
m) and subsequent cell death in cultured cardiac myocytes. (1) Priming: After H2O2 exposure (100 µmol/L), cells maintain a constant m for the cell-to-cell specific latency but at the same time undergo progressive changes in inner mitochondrial membrane structure (swelling and loss of cristae by electron microscopy). An increase of matrix calcium is required, but not sufficient, for this process. (2) Depolarization: Priming is followed by sudden depolarization of m, which is mediated by mitochondrial permeability transition pore opening, as evidenced by the concomitant release of calcein from mitochondria. This process is rapid (<4 minutes), complete, and irreversible. The duration of depolarization is constant and does not depend on the length of the priming process in any given cell. (3) Fragmentation: Along with massive mitochondrial swelling and release of cytochrome c into the cytoplasm, cells undergo surface membrane alterations, such as exposure of phosphatidylserine and eventual loss of membrane integrity and cellular fragmentation. Thus, oxidant stress elicits reproducible and stereotyped responses in cardiac cells. The priming phase, during which mitochondria undergo major ultrastructural alterations but remain functional, represents a particularly attractive target for intervention in the prevention of cell death.
Key Words: mitochondria • membrane potential • cell death • oxidative stress
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