Caloric Restriction Primes Mitochondria for Ischemic Stress by Deacetylating Specific Mitochondrial Proteins of the Electron Transport Chain

被引：76

作者：

Shinmura, Ken ^{[1
]}

Tamaki, Kayoko

Sano, Motoaki ^{[5
]}

Nakashima-Kamimura, Naomi ^{[3
]}

Wolf, Alexander M. ^{[3
]}

Amo, Taku ^{[3
,4
]}

Ohta, Shigeo ^{[3
]}

Katsumata, Yoshinori ^{[2
]}

Fukuda, Keiichi ^{[2
]}

Ishiwata, Kyoko ^{[5
]}

Suematsu, Makoto ^{[2
]}

Adachi, Takeshi ^{[3
,4
]}

机构：

[1] Keio Univ, Sch Med, Dept Internal Med, Div Geriatr Med,Shinjuku Ku, Tokyo 1608582, Japan

[2] Keio Univ, Sch Med, Dept Internal Med, Div Cardiol, Tokyo 1608582, Japan

[3] Nippon Med Sch, Grad Sch Med, Inst Dev & Aging Sci, Kawasaki, Kanagawa, Japan

[4] Natl Def Acad, Dept Appl Chem, Yokosuka, Kanagawa 239, Japan

[5] Keio Univ, Sch Med, Dept Biochem & Integrat Med Biol, Tokyo 1608582, Japan

来源：

CIRCULATION RESEARCH | 2011年 / 109卷 / 04期

关键词：

ischemia; mitochondria; nutrition; reactive oxygen species; reperfusion; FREE-RADICAL GENERATION; COMPLEX-I; RAT-HEART; REPERFUSION INJURY; OXIDATIVE STRESS; NITRIC-OXIDE; CARDIOPROTECTION; DISEASE; DYSFUNCTION; SIRTUINS;

D O I：

10.1161/CIRCRESAHA.111.243097

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Rationale: 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. Methods and 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 H2O2 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. (Circ Res. 2011;109:396-406.)

引用

页码：396 / 406

页数：11

共 58 条

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