Mitochondria, oxidative stress and the regulation of cell death

抄録

In addition to the well-known role of mitochondria in energy metabolism, regulation of cell death has recently emerged as a major function of these organelles. This, in turn, seems to be linked to their role as the major intracellular source of reactive oxygen species (ROS), which are generated at Complex I and III of the respiratory chain. Excessive ROS production has now been implicated in mtDNA mutations, ageing, and cell death. Although mitochondrial dysfunction can result in ATP depletion and necrosis, these organelles are also involved in the execution of apoptotic cell death by mechanisms which have been conserved through evolution. Hence, many lethal agents target the mitochondria and cause the release of cyto-chrome c and other 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 increase in “free” cytochrome c in the mitochondrial intermembrane space. Subsequent release of cytochrome c into the cytosol occurs by pore formation in the outer mitochondrial membrane mediated by pro-apoptotic Bcl-2 family proteins, such as tBid, Bax and Bak, or by Ca²⁺-and ROS-triggered mitochondrial permeability transition, although the latter pathway might be more closely associated with necrotic cell death. Taken together, these findings have placed the mitochondria in the focus of cell death research.