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

ECU Author/Contributor (non-ECU co-authors, if there are any, appear on document)
Ruben C. Sloan (Creator)
East Carolina University (ECU )
Web Site:
David A. Brown

Abstract: 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<0.05) and Na/Ca exchange activity was faster in diabetic when compared to non-diabetic despite no differences in respiratory control ratio and mitochondrial membrane potential between groups. Treatment of diabetic mitochondria with 2mM of the reducing agent dithiothreitol significantly decreased the sensitivity to PTP opening and normalized mitochondrial calcium uniporter activity to non-diabetic levels. These findings suggest that the augmented susceptibility to injury and enhanced cardiac dysfunction in the diabetic heart is mediated by redox-dependent shifts in mitochondrial calcium handling and that three novel mitochondria-targeted compounds administered at reperfusion may be suitable adjuvant reperfusion therapies to attenuate injury in diabetic patients. 

Additional Information

Date: 2012
Physiology, Medicine, Calcium, Diabetes, Heart
Reperfusion injury
Calcium--Physiological effect

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