Decreased Superoxide Production in Macrophages of Long-lived p66Shc Knock-out Mice

Tomilov, Alexey; Bicocca, Vincent T.; Schoenfeld, Robert; Giorgio, Marco; Migliaccio, Enrica; Ramsey, Jon J.; Hagopian, Kevork; Pelicci, Pier Giuseppe; Cortopassi, Gino A

doi:10.1074/jbc.m109.017491

Cited by 53 publications

(55 citation statements)

References 91 publications

(86 reference statements)

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“…For example, long-lived mice deficient in the p66Shc signaling molecule were recently shown to produce less superoxide in macrophages (45). However, modulation of ROS production at complex I, by means of NDI1 or other approaches, now offers a way to manipulate metazoan lifespan by mitigating a key source of age-associated damage.…”

Section: Discussionmentioning

confidence: 99%

Expression of the yeast NADH dehydrogenase Ndi1 in Drosophila confers increased lifespan independently of dietary restriction

Sanz

Soikkeli²,

Portero‐Otín³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

125

162

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Mutations in mitochondrial oxidative phosphorylation complex I are associated with multiple pathologies, and complex I has been proposed as a crucial regulator of animal longevity. In yeast, the single-subunit NADH dehydrogenase Ndi1 serves as a non-proton-translocating alternative enzyme that replaces complex I, bringing about the reoxidation of intramitochondrial NADH. We have created transgenic strains of Drosophila that express yeast NDI1 ubiquitously. Mitochondrial extracts from NDI1-expressing flies displayed a rotenone-insensitive NADH dehydrogenase activity, and functionality of the enzyme in vivo was confirmed by the rescue of lethality resulting from RNAi knockdown of complex I. NDI1 expression increased median, mean, and maximum lifespan independently of dietary restriction, and with no change in sirtuin activity. NDI1 expression mitigated the aging associated decline in respiratory capacity and the accompanying increase in mitochondrial reactive oxygen species production, and resulted in decreased accumulation of markers of oxidative damage in aged flies. Our results support a central role of mitochondrial oxidative phosphorylation complex I in influencing longevity via oxidative stress, independently of pathways connected to nutrition and growth signaling.aging | mitochondria | respiratory chain | free radicals M itochondria are key metabolic organelles whose oxidative phosphorylation (OXPHOS) system is considered to be one of the most efficient producers of bioenergy. When OX-PHOS function is compromized (e.g., by mutations or toxins), bioenergy supply and cellular homeostasis are seriously disrupted, which can be lethal.OXPHOS complex I plays a central role in the regulation of ATP production, intermediary metabolism, and apoptosis (1, 2), and mutations affecting it cause many human pathologies (3). It has also been proposed as a pacemaker of the aging process (4). Treatments inferred to decrease the production of reactive oxygen species (ROS) at the level of complex I can prolong lifespan in Drosophila (5). All these characteristics make it essential to understand better the role of complex I in vivo and its involvement in aging.Many organisms possess alternative enzymes that can bypass or replace the proton-translocating complexes of the mitochondrial respiratory chain. These include the alternative oxidases (AOX) and the NADH dehydrogenases of the Ndi and Nde families. Together these enzymes provide an alternative respiratory chain that potentially allows the maintenance of redox homeostasis and intermediary metabolism under conditions where flux through the "standard" respiratory chain is limited by high ATP levels, the action of toxins or other physiological restraints (6, 7). AOX acts as a bypass of complexes III and IV, whereas Nde or Ndi can bypass complex I.In previous studies these bypass enzymes were shown to be active when introduced into the mitochondria of higher metazoans such as mammals (8-12), arthropods (13), or nematodes (14), all of which lack endogenous alternative enzymes. Fu...

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Section: Discussionmentioning

confidence: 99%

Expression of the yeast NADH dehydrogenase Ndi1 in Drosophila confers increased lifespan independently of dietary restriction

Sanz

Soikkeli²,

Portero‐Otín³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

125

162

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“…There was a 30% increase in the lifespan of p66Shc -/ -mice (17). Furthermore, macrophages from p66Shc -/ -mice appeared to be a defect in the activation of the NADPH oxidase and, therefore, less superoxide production was observed (33). All these findings suggest a crucial role for p66Shc in the oxidative challenge.…”

mentioning

confidence: 86%

Sulfhydration of p66Shc at Cysteine59 Mediates the Antioxidant Effect of Hydrogen Sulfide

Xie

Shi²,

Xie³

et al. 2014

Antioxidants & Redox Signaling

116

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Aims: Mitochondrion is considered as the major source of intracellular reactive oxygen species (ROS). H 2 S has been reported to be an antioxidant, but its mechanism remains largely elusive. P66Shc is an upstream activator of mitochondrial redox signaling. The aim of this study was to explore whether the antioxidant effect of H 2 S is mediated by p66Shc. Results: Application of exogenous H 2 S with its donor, NaHS, or overexpression of its generating enzyme, cystathionine b-synthase, induced sulfhydration of p66Shc, but inhibited its phosphorylation caused by H 2 O 2 /D-galactose in SH-SY5Y cells or in the mice cortex. H 2 S also decreased mitochondrial ROS production and protected neuronal cells against stress-induced senescence. PKC bII and PP2A are the two key proteins to regulate p66Shc phosphorylation. Although H 2 S failed to affect the activities of these two proteins, it disrupted their association. Cysteine-59 resides in proximity to serine-36, the phosphorylation site of p66Shc. The C59S mutant attenuated the above-described biological function of H 2 S. Innovation: We revealed a novel mechanism for the antioxidant effect of H 2 S and its role in oxidative stress-related diseases. Conclusion: H 2 S inhibits mitochondrial ROS production via the sulfhydration of Cys-59 residue, which in turn, prevents the phosphorylation of p66Shc. Antioxid. Redox Signal. 21, 2531-2542.

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“…Promotion of apoptosis through p66Shc occurs by superoxide production. Transport to mitochondria and activation of p66Shc in the setting of diabetes appears to be mediated through phosphorylation by PKC␤II (1377,1378,1398,1801) but also by electrophiles such as acrolein. An increase in glucose in the medium bathing endothelial cells results in persistent activation of PKC␤II and p66Shc with increased mitochondrial ROS production persisting even after glucose levels are reduced (1377).…”

Section: Ros Effects On Nf-b Signalingmentioning

confidence: 99%

Molecular Biology of Atherosclerosis

Hopkins

2013

Physiological Reviews

389

344

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At least 468 individual genes have been manipulated by molecular methods to study their effects on the initiation, promotion, and progression of atherosclerosis. Most clinicians and many investigators, even in related disciplines, find many of these genes and the related pathways entirely foreign. Medical schools generally do not attempt to incorporate the relevant molecular biology into their curriculum. A number of key signaling pathways are highly relevant to atherogenesis and are presented to provide a context for the gene manipulations summarized herein. The pathways include the following: the insulin receptor (and other receptor tyrosine kinases); Ras and MAPK activation; TNF-␣ and related family members leading to activation of NF-B; effects of reactive oxygen species (ROS) on signaling; endothelial adaptations to flow including G protein-coupled receptor (GPCR) and integrin-related signaling; activation of endothelial and other cells by modified lipoproteins; purinergic signaling; control of leukocyte adhesion to endothelium, migration, and further activation; foam cell formation; and macrophage and vascular smooth muscle cell signaling related to proliferation, efferocytosis, and apoptosis. This review is intended primarily as an introduction to these key signaling pathways. They have become the focus of modern atherosclerosis research and will undoubtedly provide a rich resource for future innovation toward intervention and prevention of the number one cause of death in the modern world.

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Decreased Superoxide Production in Macrophages of Long-lived p66Shc Knock-out Mice

Cited by 53 publications

References 91 publications

Expression of the yeast NADH dehydrogenase Ndi1 in Drosophila confers increased lifespan independently of dietary restriction

Expression of the yeast NADH dehydrogenase Ndi1 in Drosophila confers increased lifespan independently of dietary restriction

Sulfhydration of p66Shc at Cysteine59 Mediates the Antioxidant Effect of Hydrogen Sulfide

Molecular Biology of Atherosclerosis

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