Mitochondria, oxidative stress and cell death.
In addition to the well-established role of the mitochondria in energy metabolism, regulation of cell death has recently emerged as a second major function of these organelles. This, in turn, seems to be intimately linked to their role as the major intracellular source of reactive oxygen species (ROS), which are mainly generated at Complex I and III of the respiratory chain. Excessive ROS production can lead to oxidation of macromolecules and has been implicated in mtDNA mutations, ageing, and cell death. Mitochondria-generated ROS play an important role in the release of cytochrome c and other pro-apoptotic proteins, which can trigger caspase activation and apoptosis. Cytochrome c release occurs by a two-step process that is initiated by the dissociation of the hemoprotein from its binding to cardiolipin, which anchors it to the inner mitochondrial membrane. Oxidation of cardiolipin reduces cytochrome c binding and results in an increased level of "free" cytochrome c in the intermembrane space. Conversely, mitochondrial antioxidant enzymes protect from apoptosis. Hence, there is accumulating evidence supporting a direct link between mitochondria, oxidative stress and cell death.
Ott
Martin
M
Institute of Environmental Medicine, Karolinska Institutet, S-171 77 Stockholm, Sweden.
Gogvadze
Vladimir
V
Orrenius
Sten
S
Zhivotovsky
Boris
B
D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D002308:Cardiolipins / Q000378:metabolism; D016923:Cell Death / Q000502:physiology*; D045304:Cytochromes c / Q000378:metabolism; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism
D000975:Antioxidants; D002308:Cardiolipins; D017382:Reactive Oxygen Species; D045304:Cytochromes c