Reactive oxygen species in mitochondria-mediated 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. Although mitochondrial dysfunction can cause ATP depletion and necrosis, these organelles are also involved in the regulation of apoptotic cell death 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, which can trigger caspase activation and apoptosis. Taken together, these findings have placed the mitochondria in the focus of current cell death research.