Caloric Restriction Promotes Ischemia/Reperfusion Cardioprotection Through Increased Mitochondrial Na ⁺ /Ca ²⁺ Exchange

Caloric restriction (CR) protects against cardiac ischemia/reperfusion (I/R) injury, but the underlying mechanisms remain incompletely understood. Since mitochondrial Ca ²⁺ overload is a major driver of cardiac damage during reperfusion, we investigated if enhanced mitochondrial Ca ²⁺ 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 Ca ²⁺ retention capacity when Na ⁺ ions were present, reduced H ₂ O ₂ production, and increased the expression of mitochondrial Ca ²⁺ extrusion proteins NCLX and TMEM65. In cardiomyocytes exposed to serum from CR rats, Ca ²⁺ retention capacity also increased markedly, as well and Ca ²⁺ efflux. Following I/R, CR hearts exhibited improved functional recovery, accompanied by enhanced retention and increased mitochondrial Ca ²⁺ efflux activity, as well as reduced H ₂ O ₂ production compared to AL controls. Importantly, inhibition of mitochondrial Na ⁺ /Ca ²⁺ 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 Ca ²⁺ efflux, thereby preserving mitochondrial function, limiting oxidative stress, and improving post-ischemic cardiac recovery.