Abstract
<jats:p>Caloric restriction (CR) protects against cardiac ischemia/reperfusion (I/R) injury, but the underlying mechanisms remain incompletely understood. Since mitochondrial Ca2+ overload is a major driver of cardiac damage during reperfusion, we investigated if enhanced mitochondrial Ca2+ efflux contributes toward CR-induced cardioprotection. Rats were subjected to 16 weeks of ad libitum (AL) feeding or 40% caloric restriction. CR significantly increased mitochondrial Ca2+ retention capacity when Na+ ions were present, reduced H2O2 production, and increased the expression of mitochondrial Ca2+ extrusion proteins NCLX and TMEM65. In cardiomyocytes exposed to serum from CR rats, Ca2+ retention capacity also increased markedly, as well and Ca2+ efflux. Following I/R, CR hearts exhibited improved functional recovery, accompanied by enhanced retention and increased mitochondrial Ca2+ efflux activity, as well as reduced H2O2 production compared to AL controls. Importantly, inhibition of mitochondrial Na+/Ca2+ exchange abolished the mitochondrial adaptation effects of CR, eliminating its protection against damage in cardiomyocytes and perfused hearts. These findings demonstrate that CR protects the heart from I/R injury by enhancing Na+-dependent mitochondrial Ca2+ efflux, thereby preserving mitochondrial function, limiting oxidative stress, and improving post-ischemic cardiac recovery.</jats:p>