Oxidant, mitochondria and calcium: An overview

Mitochondria are active in the continuous generation of reactive oxygen spe cies (ROS),(e.,a., superoxide), thereby favouring a situation of mitochondr ial oxidative stress. Under oxidative stress-for example, ischaemia-reoxyge nation injury to cells-mitochondria form superoxide, which in rum is conver ted to hydrogen peroxide and the potent reactive species, hydroxyl radical. Alternatively, mitochondrial superoxide may react with nitric oxide to for m potent oxidant peroxynitrite and as a consequence, mitochondrial function is altered. An increase in the release of calcium from mitochondria by oxi dants stimulates calcium-dependent enzymes such as calcium-dependent protea ses, nucleases, and phospholipases, which subsequently trigger apoptosis of the cells. In principle, calcium can leave mitochondria by different ways: by non-spec ific leakage through the inner membrane by "pore formation," by changes in the membrane lipid Chase, by reversal of the uniport influx carrier, by the specific calcium/hydrogen (or sodium) antiport system, by channel-mediated release pathways, or by a combination of two Or more of these pathways. Additionally, the release of calcium from mitochondria can also occur tithe r by oxidation of internal nicotinamide adenine nucleotides to ADP ribose a nd nicotinamide or by oxidation of thiols in membrane proteins. Once calciu m efflux has been triggered, a series of common pathways of apoptosis are i nitiated, each of which map be sufficient to destroy the cell. Apoptosis requires the active participation of cellular components, and sev eral genes have been suggested to control apoptosis. The proto-oncogene bcl -2 suppresses apoptosis through mitochondrial effects. Overexpression of bc l-2 in the mitochondrial membrane inhibits calcium efflux, but the underlyi ng mechanisms are not clearly known. Further studies are needed to explore the nature of the apoptosis-inducing pathways, the precise mechanisms of calcium efflux, the molecular partners of bcl-2 oncoproteins at the level of the outer-inner membrane contact site s, the molecular biology of the apoptosis-inducing factor formation and rel ease, and the essential molecular targets of apoptosis inducing proteases. Clarification of these issues might facilitate the understanding of mitocho ndrial response on cellular calcium dynamics under oxidant stress. CELL SIG NAL 11;2:77-85, 1999. (C) 1998 Elsevier Science Inc.