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Mitochondrial Oxidative Stress: Implications for Cell Death.

Orrenius S, Gogvadze V, Zhivotovsky B

Institute of Environmental Medicine, Karolinska Institutet, Stockholm, S-171 77 Sweden sten.orrenius@imm.ki.se.

In addition to the established role of the mitochondria in energy metabolism, regulation of cell death has emerged as a second major function of these organelles. This seems to be intimately linked to their generation of reactive oxygen species (ROS), which have been implicated in mtDNA mutations, ageing, and cell death. Mitochondrial regulation of apoptosis occurs by mechanisms, which have been conserved through evolution. Thus, many lethal agents target the mitochondria and cause release of cytochrome c and other pro-apoptotic proteins into the cytoplasm. Cytochrome c release is initiated by the dissociation of the hemoprotein from its binding to the inner mitochondrial membrane. Oxidation of cardiolipin reduces cytochrome c binding and increases the level of soluble cytochrome c in the intermembrane space. Subsequent release of the hemoprotein occurs by pore formation mediated by pro-apoptotic Bcl-2 family proteins, or by Ca(2+) and ROS-triggered mitochondrial permeability transition, although the latter pathway might be more closely associated with necrosis. Taken together, these findings have placed the mitochondria in the focus of current cell death research. Expected online publication date for the Annual Review of Pharmacology and Toxicology Volume 47 is January 6, 2007. Please see http://www.annualreviews.org/catalog/pub_dates.asp for revised estimates.

Published 10 October 2006 in Annu Rev Pharmacol Toxicol.
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