title: Regulation of apoptosis by the redox state of cytochrome c.
abstract: Cytochrome c, released from mitochondria into the cytosol, triggers formation of the apoptosome resulting in activation of caspases. This paper reviews the evidence for and against the redox state of cytochrome c regulating apoptosis, and possible mechanisms of this. Three research groups have found that the oxidized form of cytochrome c (Fe(3+)) can induce caspase activation via the apoptosome, while the reduced form (Fe(2+)) cannot. It is unclear whether this is due to the oxidized and reduced forms of cytochrome c having: (i) different affinities for Apaf-1, (ii) different abilities to activate Apaf-1 once bound, or (iii) different affinities for other components of the cell. Experiments replacing the Fe of cytochrome c with redox-inactive metals indicate that cytochrome c does not have to change redox states to activate caspases. In healthy cells, cytosolic cytochrome c is rapidly reduced by various enzymes and/or reductants, which may function to block apoptosis. However, in apoptotic cells, cytosolic cytochrome c is rapidly oxidized by mitochondrial cytochrome oxidase, to which it has access due to permeabilization of the outer membrane. Regulation of the redox state of cytochrome c potentially enables regulation of the intrinsic pathway of apoptosis at a relatively late stage.
authors.affiliation: Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge CB2 1QW, UK. gcb@bioc.cam.ac.uk
authors.forename: Guy C
authors.initials: GC
authors.lastname: Brown
authors.forename: Vilmante
authors.initials: V
authors.lastname: Borutaite
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D020169:Caspases / Q000378:metabolism; D045304:Cytochromes c / Q000737:chemistry / Q000378:metabolism*; D004789:Enzyme Activation; D006418:Heme / Q000378:metabolism; D006736:Horses; D008958:Models, Molecular; D009206:Myocardium / Q000201:enzymology; D010084:Oxidation-Reduction
chemical_list: D006418:Heme; D045304:Cytochromes c; D020169:Caspases