Mitochondrial mechanisms of neural cell apoptosis.
The importance of calcium overload, mitochondrial dysfunction, and free radical generation to neuropathological processes has been recognized for many years. Only more recently has evidence accumulated that the programmed cell death process of apoptosis plays an integral role not only in the development of the nervous system, but in the loss of cells following acute neurological insults and chronic disease. In 1996 came the landmark discovery that cytochrome c, an evolutionary old and essential component of the respiratory chain, has a second and deadly function when it escapes the mitochondrion: triggering the cell death cascade. A flurry of activity has since ensued in an effort to understand the mechanistic events associated with mitochondrial permeabilization during apoptosis and regulation by an enigmatic family of proteins characterized by homology to the proto-oncogene Bcl-2. This review discusses the evidence for various release mechanisms of apoptotic proteins (e.g. cytochrome c) from neural cell mitochondria, focusing particularly on roles for calcium, Bax, p53, and oxidative stress. The need for new drugs that act at the level of the mitochondrion to prevent apoptosis is also highlighted.
Polster
Brian M
BM
W. Harry Feinstone Department of Microbiology and Molecular Immunology, The Johns Hopkins University School of Public Health, Baltimore, Maryland, USA.
Fiskum
Gary
G
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D008928:Mitochondria / Q000502:physiology*; D008959:Models, Neurological; D009474:Neurons / Q000166:cytology* / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2; D015398:Signal Transduction / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D051028:bcl-2-Associated X Protein
D018696:Neuroprotective Agents; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D045304:Cytochromes c; D020169:Caspases; D002118:Calcium