NITRIC-OXIDE AND ITS CONGENERS IN MITOCHONDRIA - IMPLICATIONS FOR APOPTOSIS

Apoptosis is an evolutionarily conserved form of physiologic cell deat h important for tissue development and homeostasis. The causes and exe cution mechanisms of apoptosis are not completely understood. Nitric o xide (NO) and its congeners, oxidative stress, Ca2+, proteases, nuclea ses, and mitochondria are considered mediators of apoptosis. Recent fi ndings strongly suggest that mitochondria contain a factor or factors that. upon release from the destabilized organelles, induce apoptosis. We have found that oxidative stress-induced release of Ca2+ from mito chondria followed by Ca2+ reuptake (Ca2+ cycling) causes destabilizati on of mitochondria and apoptosis. The protein product of the protoonco gene bcl-2 protects mitochondria and thereby prevents apoptosis. We ha ve also found that NO and its congeners can induce Ca2+ release from m itochondria. Thus, nitrogen monoxide ((NO)-N-.) binds to cytochrome ox idase, blocks respiration, and thereby causes mitochondrial deenergiza tion and Ca2+ release. Peroxynitrite (ONOO-), on the other hand, cause s Ca2+ release from mitochondria by stimulating a specific Ca2+ releas e pathway. This pathway requires oxidized nicotinamide adenine dinucle otide (NAD(+)) hydrolysis to adenosine diphosphate ribose and nicotina mide. NAD(+) hydrolysis is only possible when some vicinal thiols are cross-linked. ONOO- is able to oxidize them. Our findings suggest that NO and its congeners can induce apoptosis by destabilizing mitochondr ia via deenergization and/or by inducing a specific Ca2+ release follo wed by Ca2+ cycling.