Distinct Effects of Mitochondrial Na/Ca Exchanger Inhibition and Ca Uniporter Activation on Ca Sparks and Arrhythmogenesis in Diabetic Rats.

Background Mitochondrial dysfunction contributes to the cardiac remodeling triggered by type 2 diabetes (T2D). Mitochondrial Ca concentration ([Ca]) modulates the oxidative state and cytosolic Ca regulation. Thus, we investigated how T2D affects mitochondrial Ca fluxes, the downstream consequences on myocyte function, and the effects of normalizing mitochondrial Ca transport. Methods and Results We compared myocytes/hearts from transgenic rats with late-onset T2D (rats that develop late-onset T2D due to heterozygous expression of human amylin in the pancreatic β-cells [HIP] model) and their nondiabetic wild-type (WT) littermates. [Ca] was significantly lower in myocytes from diabetic HIP rats compared with WT cells. Ca extrusion through the mitochondrial Na/Ca exchanger (mitoNCX) was elevated in HIP versus WT myocytes, particularly at moderate and high [Ca], while mitochondrial Ca uptake was diminished. Mitochondrial Na concentration was comparable in WT and HIP rat myocytes and remained remarkably stable while manipulating mitoNCX activity. Lower [Ca] was associated with oxidative stress, increased sarcoplasmic reticulum Ca leak in the form of Ca sparks, and mitochondrial dysfunction in T2D hearts. MitoNCX inhibition with CGP-37157 reduced oxidative stress, Ca spark frequency, and stress-induced arrhythmias in HIP rat hearts while having no significant effect in WT rats. In contrast, activation of the mitochondrial Ca uniporter with SB-202190 enhanced spontaneous sarcoplasmic reticulum Ca release and had no significant effect on arrhythmias in both WT and HIP rat hearts. Conclusions [Ca] is reduced in myocytes from rats with T2D due to a combination of exacerbated mitochondrial Ca extrusion through mitoNCX and impaired mitochondrial Ca uptake. Partial mitoNCX inhibition limits sarcoplasmic reticulum Ca leak and arrhythmias in T2D hearts, whereas mitochondrial Ca uniporter activation does not.