Abstract
Cardioprotection methods have been developed to protect the heart against deleterious effects of ischemia reperfusion (IR), among them, postconditioning (PC) was shown to decrease infarct size (IS). Thus, it was shown that deacetylation, a post-translational modification, was crucial for PC success. Our lab recently shown that modification on acetylation level of cyclophilin D (CypD) by sirtuin 3 (SIRT3), a mitochondrial deacetylase, modifies the efficiency of ischemic-postconditionning (IPC). Indeed, it was shown that in absence of SIRT3, CypD is hyperacetylated leading to mPTP opening and cell death and inefficacy of IPC. Moreover, numerous studies have linked the lack of SIRT3 with aging associated pathologies. The goal of this study was to decipher the impact of CypD deacetylation mediated by SIRT3 in PC in the aging context. We submitted young (2 months) and old (≤ 12 months) mice, WT and SIRT3 KO, to IR and IPC. IS were quantified, and mitochondrial protein acetylation was evaluated. In parallel, basal mitochondrial functions and protein acetylation were assessed, as well as deacetylase activity, to estimate the impact of aging. Our results enlightened the importance of SIRT3 for PC success in young mice (25% IS reduction), that is lost in the old mice. We reported no more modification of the acetylation profile neither after IR or IPC in old mice. Moreover, we quantified a significant decrease in deacetylase activity with age (25%), associated to a significant decrease in NAD+ content (60%) with no basal mitochondrial function modification in old mice that could be associated to the loss of IPC efficiency. In accordance with what we demonstrated in young mice, the failure of IPC in old mice could be explained by a lack of CypD deacetylation following IPC stimulus, linked with an alteration of the deacetylase mitochondrial activity associated to a significant decrease in NAD+ mitochondrial content.
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