Possible Pathway of Na⁺ Flux into Mitochondria in Ischemic Heart

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Previous studies showed that myocardial Na⁺ overload during ischemia directly induced mitochondrial damage. The pathway for Na⁺ flux into mitochondria remains unclear. We examined possible routes for Na⁺ flux into mitochondria in the ischemic heart. Isolated perfused rat hearts were subjected to 15- to 35-min ischemia followed by 60-min reperfusion and then Na⁺ content and respiratory function in mitochondria of the ischemic heart were determined. The mitochondrial Na⁺ content of the ischemic heart was ischemic duration-dependently increased, associated with a reduction in mitochondrial respiratory function. To mimic induction of mitochondrial Na⁺ overload in vitro, isolated mitochondria were incubated with 6.25 to 50 mM NaCl or sodium lactate, a metabolite of anaerobic glycolysis, in the presence and absence of a mitochondrial Na⁺/Ca²⁺ exchanger inhibitor CGP37157 and a monocarboxylate transporter (MCT) inhibitor α-cyano-4-hydroxy cinnamic acid (CHCA). Incubation of mitochondria with NaCl or sodium lactate increased the mitochondrial Na⁺ concentration. This increase in mitochondrial Na⁺ was partially attenuated by the presence of either inhibitor. Combined treatment of mitochondria with both inhibitors attenuated sodium lactate-induced increase in Na⁺ content to a greater degree than that treated with either agent. These results suggest that mitochondrial Na⁺/Ca²⁺ exchanger and MCT inhibitor-sensitive Na⁺ transporter are possible pathways for the mitochondrial Na⁺ overload in the ischemic myocardium.