Diabetic Cardiac Energetics How does mitochondrial function change in diabetic rat heart?

Abstract

Developed countries are experiencing a diabetes epidemic, and approximately 80% of diabetics die from heart disease. While the ultimate cause of heart failure remains unknown, diabetic hearts show a progressive decline in cardiac efficiency and cardiac energy metabolism. However, how this inefficiency of the heart develops remains unknown. This work explores the role of cardiac mitochondria in diabetic cardiomyopathy. Using high resolution respirometers coupled with purpose-built fluorimeters, mitochondrial function was assessed in heart homogenates by measuring ATP production, mitochondrial membrane potential (ΔΨ), and net ROS output from Streptozotocin (STZ) induced- diabetic Sprague- Dawley rats. Relative to sham/control rats (saline injected), per unit mass of homogenate, STZ-diabetic hearts showed a depression in ATP synthesis capacity of almost 1/3 relative to control heart homogenates. STZ-diabetic rats also showed inefficient ATP production, with a decreased efficiency of energy conservation of 12%. The coupled fluorimeters and respirometers also permitted determination of the ATP dynamics in anoxic states. Anoxic STZ-diabetic heart tissues showed similar capacities to hydrolyse ATP as controls, and addition of oligomycin revealed that this consumption was due to reversal of the mitochondrial F1/F0 ATP-synthase. Therefore, mitochondria in diabetic hearts produce much less ATP in normoxia, yet can consume as much ATP in anoxic states such as during infarcts. STZ-Diabetic cardiac mitochondria also appeared to show a greater net ROS release relative to oxygen consumed (ROS/O) in phosphorylating states with Complex I and II substrates. This respiration state most closely reflects in vivo mitochondrial function and provides evidence for the involvement of mitochondrial derived ROS in the depression of cardiac performance in diabetic cardiomyopathy. While ΔΨ did not differ between groups, the time to develop ΔΨ with the onset of oxidative phosphorylation was protracted in STZ-diabetic mitochondria, and this may impair ATP synthesis with inter-beat fluctuations in ADP. These data indicate that excessive ROS outputs, depressed oxidative phosphorylation capacities and efficiencies, and potential delays in the time to develop the ΔΨ may all contribute to mitochondrial dysfunction in diabetes. These results provided a clearer picture of mitochondrial dysfunction in diabetic cardiomyopathy.