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

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. Conclusions: These results strongly suggest that CR primes mitochondria for stress resistance by deacety-lating 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. T he prevalence of cardiovascular diseases increases with age. 1 Mortality of coronary artery disease in the elderly is higher than that in the middle-aged. 2,3 Consistent with clinical investigations, experimental studies demonstrate that hearts from senescent animals are more susceptible to ischemia than those from young animals. 4 – 6 Both age-related increased prevalence of systemic diseases, referred to as cardiovascular risk factors, and development of cardiovascular aging contribute to the association between aging and cardiovascular diseases. 1 Therefore , development of novel therapeutics for the purpose of controlling cardiovascular aging is urgently required to provide for population aging in developed countries. Caloric restriction (CR) has been widely investigated in experimental animals as a powerful intervention that can prevent and reverse age-related changes. 7–9 The daily caloric intake in CR-treated animals was 50% to 70% of the average food intake of animals fed ad libitum (AL). Although there is no evidence stating that CR prolongs lifespan in humans, it markedly increases life span in several species, including rhesus monkey. 7,10 In addition, there is mounting evidence that CR profoundly affects the physiological and pathophys-iological alterations associated with aging. 7–11 We have demonstrated that both short-term (4 weeks) and prolonged (6 months) CR improves myocardial ischemic tolerance in rats of different ages. 6,12 In the short-term CR setting, we have established an obligatory role for the activation of adiponectin-AMP activated protein kinase sig-naling in CR-induced cardioprotection. 13 However, the mech-anism(s) by which prolonged CR confers cardioprotection remains unknown. 12 In the past decade, silent information regulator (Sir) 2, a longevity gene, has been reported to mediate lifespan extension by CR in lower organisms such as Caenorhabditis elegans. 14 –16 In addition, recent …