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