Sirt3 Mediates Reduction of Oxidative Damage and Prevention of Age-related Hearing Loss under Caloric Restriction

By Shinichi Someya, Wei Yu, W. Hallows, Jinze Xu, J. Vann, C. Leeuwenburgh, M. Tanokura, J. Denu, Thomas A. Prolla. Cell, 2010

1,156 citations recorded by the source corpus.

SUMMARY Caloric restriction (CR) extends the lifespan and healthspan of a variety of species, and slows the progression of age-related hearing loss (AHL), a common age-related disorder associated with oxidative stress. Here we report that CR reduces oxidative DNA damage in multiple tissues and prevents AHL in wild-type mice, but fails to modify these phenotypes in mice lacking the mitochondrial deacetylase Sirt3, a member of the sirtuin family. In response to CR, Sirt3 directly deacetylates and activates mitochondrial isocitrate dehydrogenase 2 (Idh2), leading to increased NADPH levels and an increased ratio of reduced to oxidized glutathione in mitochondria. In cultured cells, overexpression of Sirt3 and/or Idh2 increases NADPH levels and protects from oxidative stress-induced cell death. Therefore, our findings identify Sirt3 as an essential player in enhancing the mitochondrial glutathione antioxidant defense system during CR, and suggest that Sirt3-dependent mitochondrial adaptations may be a central mechanism of aging retardation in mammals.

Subfields: Geriatrics and Gerontology, Molecular Biology, Physiology

View Paper: https://www.semanticscholar.org/paper/d90cb2fe4eaa9501a5df715d2c9c288fad2b40ed

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Citations in the corpus

NAD(H) and NADP(H) Redox Couples and Cellular Energy Metabolism (2018, background): “As expected, IDH2 silencing also decreased NADPH levels (147), while IDH2 overexpression increased NADPH levels and protected against oxidative stress-induced cell death in HEK293 cells (121).”
Calorie restriction and SIRT3 trigger global reprogramming of the mitochondrial protein acetylome. (2013, background): “, 2010) and both deacetylates and regulates the function of several mitochondrial proteins in response to fasting and/or CR, including OTC, LCAD, HMGCS2, and IDH2 (Hallows et al., 2011; Hirschey et al., 2010; Shimazu et al., 2010; Someya et al., 2010).”
The hallmarks of aging. (2013, background): “Interestingly, the mitochondria-located sirtuin SIRT3 has been reported to mediate some of the beneficial effects of dietary restriction (DR) in longevity, though its effects are not due to histone modifications but, rather, due to the deacetylation of mitochondrial proteins (Someya et al., 2010).”
Therapeutic potential of NAD-boosting molecules: the in vivo evidence (2018, neutral): “…et al., 2011); SIRT3 regulates OXPHOS (Ahn et al., 2008), fatty acid oxidation (Hirschey et al., 2010), ketogenesis (Shimazu et al., 2010), and defense against oxidative stress (Finley et al., 2011; Someya et al., 2010); and SIRT6 controls gluconeogenesis (Dominy et al., 2012; Zhang et al., 2014).”
SIRT3 Deficiency and Mitochondrial Protein Hyperacetylation Accelerate the Development of the Metabolic Syndrome (2011, neutral): “…group of mitochondrial abnormalities including reduced fatty acid oxidation (Hallows et al., 2011; Hirschey et al., 2010), lower oxidative phosphorylation (Ahn et al., 2008), and increased reactive oxygen species (Kim et al., 2010; Qiu et al., 2010; Someya et al., 2010; Tao et al., 2010).”
Caloric restriction. (2011, background): “Many other cancers are impacted by CR, including cancers of the liver (Fu et al., 1994; Kolaja et al., 1996), pituitary (Spady et al., 1998; Stewart et al., 2005) skin (Stewart et al., 2005; Xie et al., 2007), colon (Wheatley et al., 2008) and lymph system.”
Circadian Clock NAD+ Cycle Drives Mitochondrial Oxidative Metabolism in Mice (2013, methodology): “W. Yu, K. E. Dittenhafer-Reed, J. M. Denu, SIRT3 protein deacetylates isocitrate dehydrogenase 2 (IDH2) and regulates mitochondrial redox status.”
NAD+ metabolism: pathophysiologic mechanisms and therapeutic potential (2020, background): “SIRT3mediated deacetylation of IDH2 increases the generation of mitochondrial NADPH, which elevates the reduced GSH levels.(138) Simultaneously, SIRT3 can not only induce the expression of antioxidant enzymes by activating the FOXO3a, but also enhance the activation of SOD2 and catalase via NAD-depe”
SIRT3 opposes reprogramming of cancer cell metabolism through HIF1α destabilization (2011, background): “Additionally, SIRT3 can directly target IDH2, influencing cellular redox status, and SOD2, activating mitochondrial ROS scavenging (Qiu et al., 2010; Someya et al., 2010; Tao et al., 2010).”
Sirtuins as regulators of metabolism and healthspan (2012, background): “In response to caloric restriction, SIRT3 deacetylates and thereby activates isocitrate dehydrogenase 2 (IDH2; which is involved in the tricarboxylic acid cycle (TCA cycle)”
SIRT1 and other sirtuins in Metabolism (2013, background): “As for other sirtuins, knocking out the mitochondrial SIRT3 prevents the protective effect of CR against neuronal degeneration, leading to hearing loss [36].”