title: Caloric restriction primes mitochondria for ischemic stress by deacetylating specific mitochondrial proteins of the electron transport chain.
abstract: BACKGROUND
  Caloric restriction (CR) confers cardioprotection against ischemia/reperfusion injury. However, the exact mechanism(s) underlying CR-induced cardioprotection remain(s) unknown. Recent evidence indicates that Sirtuins, NAD(+)-dependent deacetylases, regulate various favorable aspects of the CR response. Thus, we hypothesized that deacetylation of specific mitochondrial proteins during CR preserves mitochondrial function and attenuates production of reactive oxygen species during ischemia/reperfusion.
  
  
  OBJECTIVE
  The objectives of the present study were (1) to investigate the effect of CR on mitochondrial function and mitochondrial proteome and (2) to investigate what molecular mechanisms mediate CR-induced cardioprotection.
  
  
  RESULTS
  Male 26-week-old Fischer344 rats were randomly divided into ad libitum-fed and CR (40% reduction) groups for 6 months. No change was observed in basal mitochondrial function, but CR preserved postischemic mitochondrial respiration and attenuated postischemic mitochondrial H(2)O(2) production. CR decreased the level of acetylated mitochondrial proteins that were associated with enhanced Sirtuin activity in the mitochondrial fraction. We confirmed a significant decrease in the acetylated forms of NDUFS1 and cytochrome bc1 complex Rieske subunit in the CR heart. Low-dose resveratrol treatment mimicked the effect of CR on deacetylating them and attenuated reactive oxygen species production during anoxia/reoxygenation in cultured cardiomyocytes without changing the expression levels of manganese superoxide dismutase. Treatment with nicotinamide completely abrogated the effect of low-dose resveratrol.
  
  
  CONCLUSIONS
  These results strongly suggest that CR primes mitochondria for stress resistance by deacetylating specific mitochondrial proteins of the electron transport chain. Targeted deacetylation of NDUFS1 and/or Rieske subunit might have potential as a novel therapeutic approach for cardioprotection against ischemia/reperfusion.
authors.affiliation: Division of Geriatric Medicine, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan. shimmura@sc.itc.keio.ac.jp
authors.forename: Ken
authors.initials: K
authors.lastname: Shinmura
authors.forename: Kayoko
authors.initials: K
authors.lastname: Tamaki
authors.forename: Motoaki
authors.initials: M
authors.lastname: Sano
authors.forename: Naomi
authors.initials: N
authors.lastname: Nakashima-Kamimura
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Wolf
authors.forename: Taku
authors.initials: T
authors.lastname: Amo
authors.forename: Shigeo
authors.initials: S
authors.lastname: Ohta
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Katsumata
authors.forename: Keiichi
authors.initials: K
authors.lastname: Fukuda
authors.forename: Kyoko
authors.initials: K
authors.lastname: Ishiwata
authors.forename: Makoto
authors.initials: M
authors.lastname: Suematsu
authors.forename: Takeshi
authors.initials: T
authors.lastname: Adachi
mesh_terms: D000107:Acetylation; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D015153:Blotting, Western; D031204:Caloric Restriction; D002478:Cells, Cultured; D004195:Disease Models, Animal; D045222:Electron Transport Chain Complex Proteins / Q000378:metabolism*; D014450:Electron Transport Complex III / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D009243:NAD / Q000378:metabolism; D009245:NADH Dehydrogenase / Q000378:metabolism; D009536:Niacinamide / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D040901:Proteomics; D051381:Rats; D011916:Rats, Inbred F344; D000077185:Resveratrol; D037761:Sirtuins / Q000378:metabolism*; D013267:Stilbenes / Q000494:pharmacology
chemical_list: D000975:Antioxidants; D045222:Electron Transport Chain Complex Proteins; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; C037989:Rieske iron-sulfur protein; D013267:Stilbenes; D009243:NAD; D009536:Niacinamide; D006861:Hydrogen Peroxide; D009245:NADH Dehydrogenase; D037761:Sirtuins; D014450:Electron Transport Complex III; D000077185:Resveratrol