title: Sirt3 mediates reduction of oxidative damage and prevention of age-related hearing loss under caloric restriction.
abstract: Caloric restriction (CR) extends the life span and health span 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.
authors.affiliation: Departments of Genetics and Medical Genetics, University of Wisconsin, Madison, 53706, USA.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Someya
authors.forename: Wei
authors.initials: W
authors.lastname: Yu
authors.forename: William C
authors.initials: WC
authors.lastname: Hallows
authors.forename: Jinze
authors.initials: J
authors.lastname: Xu
authors.forename: James M
authors.initials: JM
authors.lastname: Vann
authors.forename: Christiaan
authors.initials: C
authors.lastname: Leeuwenburgh
authors.forename: Masaru
authors.initials: M
authors.lastname: Tanokura
authors.forename: John M
authors.initials: JM
authors.lastname: Denu
authors.forename: Tomas A
authors.initials: TA
authors.lastname: Prolla
mesh_terms: D000375:Aging / Q000378:metabolism*; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D031204:Caloric Restriction; D004249:DNA Damage; D005260:Female; D005978:Glutathione / Q000378:metabolism; D034381:Hearing Loss / Q000517:prevention & control*; D007521:Isocitrate Dehydrogenase / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism*; D018384:Oxidative Stress; D056566:Sirtuin 3 / Q000235:genetics / Q000378:metabolism*
chemical_list: D000975:Antioxidants; C525046:Sirt3 protein, mouse; D007521:Isocitrate Dehydrogenase; D056566:Sirtuin 3; D005978:Glutathione