The pathophysiology of mitochondrial cell death.
In the mitochondrial pathway of apoptosis, caspase activation is closely linked to mitochondrial outer membrane permeabilization (MOMP). Numerous pro-apoptotic signal-transducing molecules and pathological stimuli converge on mitochondria to induce MOMP. The local regulation and execution of MOMP involve proteins from the Bcl-2 family, mitochondrial lipids, proteins that regulate bioenergetic metabolite flux, and putative components of the permeability transition pore. MOMP is lethal because it results in the release of caspase-activating molecules and caspase-independent death effectors, metabolic failure in the mitochondria, or both. Drugs designed to suppress excessive MOMP may avoid pathological cell death, and the therapeutic induction of MOMP may restore apoptosis in cancer cells in which it is disabled. The general rules governing the pathophysiology of MOMP and controversial issues regarding its regulation are discussed.
Division of Cellular Immunology, La Jolla Institute for Allergy and Immunology, 10355 Science Center Drive, San Diego, CA 92121, USA. doug@liai.org
Douglas R
DR
Green
Guido
G
Kroemer
D000818:Animals; D017209:Apoptosis; D004194:Disease / Q000209:etiology*; D006801:Humans; D007425:Intracellular Membranes / Q000502:physiology*; D008928:Mitochondria / Q000502:physiology*; D008954:Models, Biological; D009369:Neoplasms / Q000503:physiopathology; D010539:Permeability; D011506:Proteins / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction; D014764:Viral Proteins / Q000378:metabolism; D018406:Virus Physiological Phenomena
D011506:Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D014764:Viral Proteins