The Physiological and Pathological Role of Mitochondrial Calcium in the Diabetic Heart

Diabetic patients are more susceptible to ischemia/reperfusion injury and cardiac dysfunction likely due alterations in mitochondrial calcium handling. The purpose of this work was to determine if redox-dependent changes in permeability transition pore opening and mitochondrial calcium transients contribute to augmented injury and dysfunction in diabetic hearts. Langendorff-perfused streptozotocin-induced diabetic hearts were more susceptible to ischemia/reperfusion injury, with infarct sizes of 60±4% of the area-at-risk (vs. 46±2% in non-diabetics; P<0.05). Administration of 5uM NIM811 (non-immunosuppressive derivative of cyclosporine A), 1nM Bendavia (mitochondria-targeted antioxidant) or 1 uM Minocycline (blocker of mitochondrial Ca influx) at the onset of reperfusion reduced diabetic infarct sizes (P<0.05). Mitochondria isolated from the left ventricles of diabetic rats displayed greater sensitivity to Ca-induced permeability transition pore opening (P<0.05). Mitochondrial Ca uptake was slower in diabetic when compared to non-diabetic mitochondria (P