title: Caspase cleavage of cytochrome c1 disrupts mitochondrial function and enhances cytochrome c release.
abstract: Mitochondrial catastrophe can be the cause or consequence of apoptosis and is associated with a number of pathophysiological conditions. The exact relationship between mitochondrial catastrophe and caspase activation is not completely understood. Here we addressed the underlying mechanism, explaining how activated caspase could feedback to attack mitochondria to amplify further cytochrome c (cyto.c) release. We discovered that cytochrome c1 (cyto.c1) in the bc1 complex of the mitochondrial respiration chain was a novel substrate of caspase 3 (casp.3). We found that cyto.c1 was cleaved at the site of D106, which is critical for binding with cyto.c, following apoptotic stresses or targeted expression of casp.3 into the mitochondrial intermembrane space. We demonstrated that this cleavage was closely linked with further cyto.c release and mitochondrial catastrophe. These mitochondrial events could be effectively blocked by expressing non-cleavable cyto.c1 (D106A) or by caspase inhibitor z-VAD-fmk. Our results demonstrate that the cleavage of cyto.c1 represents a critical step for the feedback amplification of cyto.c release by caspases and subsequent mitochondrial catastrophe.
authors.affiliation: The Joint Laboratory of Apoptosis and Cancer Biology, The National Key Laboratory of Biomembrane and Membrane Biotechnology, Chinese Academy of Sciences, Beijing, China.
authors.forename: Yushan
authors.initials: Y
authors.lastname: Zhu
authors.forename: Min
authors.initials: M
authors.lastname: Li
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Wang
authors.forename: Haijing
authors.initials: H
authors.lastname: Jin
authors.forename: Shusen
authors.initials: S
authors.lastname: Liu
authors.forename: Jianxin
authors.initials: J
authors.lastname: Xu
authors.forename: Quan
authors.initials: Q
authors.lastname: Chen
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000595:Amino Acid Sequence; D000818:Animals; D053148:Caspase 3 / Q000378:metabolism*; D061945:Caspase Inhibitors; D020134:Catalytic Domain; D045304:Cytochromes c / Q000378:metabolism*; D003575:Cytochromes c1 / Q000378:metabolism*; D004579:Electron Transport; D004789:Enzyme Activation; D025461:Feedback, Physiological; D006367:HeLa Cells; D006801:Humans; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D008928:Mitochondria / Q000201:enzymology* / Q000502:physiology; D008969:Molecular Sequence Data; D010084:Oxidation-Reduction; D010085:Oxidative Phosphorylation; D059748:Proteolysis; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D013379:Substrate Specificity; D013384:Succinate Cytochrome c Oxidoreductase / Q000378:metabolism; D014162:Transfection
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D061945:Caspase Inhibitors; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D045304:Cytochromes c; D003575:Cytochromes c1; D013384:Succinate Cytochrome c Oxidoreductase; D053148:Caspase 3