Nitric oxide and its congeners in mitochondria: implications for apoptosis.
Apoptosis is an evolutionarily conserved form of physiologic cell death important for tissue development and homeostasis. The causes and execution mechanisms of apoptosis are not completely understood. Nitric oxide (NO) and its congeners, oxidative stress, Ca2+, proteases, nucleases, and mitochondria are considered mediators of apoptosis. Recent findings 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 mitochondria followed by Ca2+ reuptake (Ca2+ cycling) causes destabilization of mitochondria and apoptosis. The protein product of the protooncogene bcl-2 protects mitochondria and thereby prevents apoptosis. We have also found that NO and its congeners can induce Ca2+ release from mitochondria. Thus, nitrogen monoxide (.NO) binds to cytochrome oxidase, blocks respiration, and thereby causes mitochondrial deenergization and Ca2+ release. Peroxynitrite (ONOO-), on the other hand, causes Ca2+ release from mitochondria by stimulating a specific Ca2+ release pathway. This pathway requires oxidized nicotinamide adenine dinucleotide (NAD+) hydrolysis to adenosine diphosphate ribose and nicotinamide. 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 mitochondria via deenergization and/or by inducing a specific Ca2+ release followed by Ca2+ cycling.
Richter
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Laboratory of Biochemistry, Swiss Federal Institute of Technology, Zürich, Switzerland. richter@bc.biol.ethz.ch
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D003576:Electron Transport Complex IV / Q000378:metabolism; D019254:Genes, bcl-2; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D009243:NAD / Q000378:metabolism; D009566:Nitrates / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism
D009566:Nitrates; D017382:Reactive Oxygen Species; D009243:NAD; C039642:peroxynitric acid; D009569:Nitric Oxide; D003576:Electron Transport Complex IV; D002118:Calcium