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.

Reactive oxygen species mediate crosstalk between NF-κB and JNK

“…A recent study 65 indicated that activated caspase 3 cleaves the p75 subunit of complex I of the mitochondrial electron transport chain, resulting in ROS accumulation. Similarly, Giorgio et al 66 have shown that proapoptotic signals induce release of p66 Shc from a putative inhibitory complex, which in turn oxidizes reduced cytochrome c, thereby generating ROS. On the other hand, Ventura et al 53 have reported that TNFa-induced ROS accumulation is abolished in cells lacking JNK1 and JNK2, indicating that a central role for JNK in ROS accumulation.…”

Free Radicals: Properties, Sources, Targets, and Their Implication in Various Diseases

“…Most of the p66Shc is located in cytoplasm with a small fraction localized in the mitochondrial intermembrane space. Upon oxidative stress, p66Shc translocates to mitochondrial intermembrane space, where it associates with cytochromec, thus inducing ROS generation [65].…”

P66SHC deletion improves fertility and progeric phenotype of late-generation TERC-deficient mice but not their short lifespan

“…P66SHC protein is the largest isoform encoded by the ShcA locus, typical of vertebrates, and it sustains intracellular levels of ROS (Giorgio et al ., 2005 Gertz & Steegborn, 2010) and regulates redox signaling pathways (Frijhoff et al ., 2014), mitochondrial apoptosis (Migliaccio et al ., 2006), and aging (Trinei et al ., 2009). P66SHC null mice (p66SHC −/− ) develop normally and resulted to be protected from aging‐associated diseases, such as atherosclerosis (Martin‐Padura et al ., 2008), diabetes compliances (Menini et al ., 2007), onset (Tomilov et al ., 2011), cognitive decline (Berry et al ., 2007), and neurodegeneration (Savino et al ., 2013).…”