title: Electron transfer between cytochrome c and p66Shc generates reactive oxygen species that trigger mitochondrial apoptosis.
abstract: Reactive oxygen species (ROS) are potent inducers of oxidative damage and have been implicated in the regulation of specific cellular functions, including apoptosis. Mitochondrial ROS increase markedly after proapoptotic signals, though the biological significance and the underlying molecular mechanisms remain undetermined. P66Shc is a genetic determinant of life span in mammals, which regulates ROS metabolism and apoptosis. We report here that p66Shc is a redox enzyme that generates mitochondrial ROS (hydrogen peroxide) as signaling molecules for apoptosis. For this function, p66Shc utilizes reducing equivalents of the mitochondrial electron transfer chain through the oxidation of cytochrome c. Redox-defective mutants of p66Shc are unable to induce mitochondrial ROS generation and swelling in vitro or to mediate mitochondrial apoptosis in vivo. These data demonstrate the existence of alternative redox reactions of the mitochondrial electron transfer chain, which evolved to generate proapoptotic ROS in response to specific stress signals.
authors.affiliation: Experimental Oncology Department, European Institute of Oncology, Milan, Italy. marco.giorgio@ifom-ieo-campus.it
authors.forename: Marco
authors.initials: M
authors.lastname: Giorgio
authors.forename: Enrica
authors.initials: E
authors.lastname: Migliaccio
authors.forename: Francesca
authors.initials: F
authors.lastname: Orsini
authors.forename: Demis
authors.initials: D
authors.lastname: Paolucci
authors.forename: Maurizio
authors.initials: M
authors.lastname: Moroni
authors.forename: Cristina
authors.initials: C
authors.lastname: Contursi
authors.forename: Giovanni
authors.initials: G
authors.lastname: Pelliccia
authors.forename: Lucilla
authors.initials: L
authors.lastname: Luzi
authors.forename: Saverio
authors.initials: S
authors.lastname: Minucci
authors.forename: Massimo
authors.initials: M
authors.lastname: Marcaccio
authors.forename: Paolo
authors.initials: P
authors.lastname: Pinton
authors.forename: Rosario
authors.initials: R
authors.lastname: Rizzuto
authors.forename: Paolo
authors.initials: P
authors.lastname: Bernardi
authors.forename: Francesco
authors.initials: F
authors.lastname: Paolucci
authors.forename: Pier Giuseppe
authors.initials: PG
authors.lastname: Pelicci
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002478:Cells, Cultured; D045304:Cytochromes c / Q000378:metabolism*; D004579:Electron Transport; D006861:Hydrogen Peroxide / Q000378:metabolism; D007425:Intracellular Membranes / Q000378:metabolism; D051379:Mice; D008930:Mitochondria, Liver / Q000378:metabolism*; D008969:Molecular Sequence Data; D009154:Mutation; D010084:Oxidation-Reduction; D010539:Permeability; D017434:Protein Structure, Tertiary; D017382:Reactive Oxygen Species / Q000378:metabolism*; D055765:Shc Signaling Adaptor Proteins; D015398:Signal Transduction; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D017382:Reactive Oxygen Species; D055765:Shc Signaling Adaptor Proteins; C528034:Shc1 protein, mouse; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D045304:Cytochromes c; D006861:Hydrogen Peroxide