Mitochondrial dysfunction is a major factor in heart failure (HF). A pronounced variability of mitochondrial electron transport chain (ETC) defects is reported to occur in severe acquired cardiomyopathies without a consistent trend for depressed activity or expression. The aim of this study was to define the defect in the integrative function of cardiac mitochondria in coronary microembolization-induced HF. Studies were performed in the canine coronary microembolization-induced HF model of moderate severity. Oxidative phosphorylation was assessed as the integrative function of mitochondria, using a comprehensive variety of substrates in order to investigate mitochondrial membrane transport, dehydrogenase activity and electron-transport coupled to ATP synthesis. The supramolecular organization of the mitochondrial ETC also was investigated by native gel electrophoresis. We found a dramatic decrease in ADP-stimulated respiration that was not relieved by an uncoupler. Moreover, the ADP/O ratio was normal, indicating no defect in the phosphorylation apparatus. The data point to a defect in oxidative phosphorylation within the ETC. However, the individual activities of ETC complexes were normal. The amount of the supercomplex consisting of complex I/complex III dimer/complex IV, the major form of respirasome considered essential for oxidative phosphorylation, was decreased. We propose that the mitochondrial defect lies in the supermolecular assembly rather than in the individual components of the ETC.

Chronic hyperglycemia causes structural alterations of proteins through the Maillard reaction. In diabetes, methylglyoxal (MGO)-induced hydroimidazolones are the predominant modification. In contrast to acute hyperglycemia, mitochondrial respiration is depressed in chronic diabetes. To determine whether MGO-derived protein modifications result in abnormalities in mitochondrial bioenergetics and superoxide formation, proteomics and functional studies were performed in renal cortical mitochondria isolated from rats with 2, 6, and 12 mo of streptozotocin-induced diabetes. MGO-modified proteins belonged to the following two pathways: 1) oxidative phosphorylation and 2) fatty acid β-oxidation. Two of these proteins were identified as components of respiratory complex III, the major site of superoxide production in health and disease. Mitochondria from rats with diabetes exhibited a diminution of oxidative phosphorylation. A decrease in the respiratory complex III activity was significantly correlated with the quantity of MGO-derived hydroimidazolone present on mitochondrial proteins in both diabetic and control animals. In diabetes, isolated renal mitochondria produced significantly increased quantities of superoxide and showed evidence of oxidative damage. Administration of aminoguanidine improved mitochondrial respiration and complex III activity and decreased oxidative damage to mitochondrial proteins. Therefore, posttranslational modifications of mitochondrial proteins by MGO may represent pathogenic events leading to mitochondria-induced oxidative stress in the kidney in chronic diabetes.

This review focuses on the evidence accumulated in humans and animal models to the effect that mitochondria are key players in the progression of heart failure (HF). Mitochondria are the primary source of energy in the form of adenosine triphosphate that fuels the contractile apparatus, and are thus essential for the pumping activity of the heart. We evaluate changes in mitochondrial morphology and alterations in the main components of mitochondrial energetics, such as substrate utilization and oxidative phosphorylation coupled with the level of respirasomes, in the context of their contribution to the chronic energy deficit and mechanical dysfunction in HF.

Mitochondrial reactive oxygen species (ROS) cause kidney damage in diabetes. We investigated the source and site of ROS production by kidney cortical tubule mitochondria in streptozotocin-induced type 1 diabetes in rats. In diabetic mitochondria, the increased amounts and activities of selective fatty acid oxidation enzymes is associated with increased oxidative phosphorylation and net ROS production with fatty acid substrates (by 40% and 30%, respectively), whereas pyruvate oxidation is decreased and pyruvate-supported ROS production is unchanged. Oxidation of substrates that donate electrons at specific sites in the electron transport chain (ETC) is unchanged. The increased maximal production of ROS with fatty acid oxidation is not affected by limiting the electron flow from complex I into complex III. The maximal capacity of the ubiquinol oxidation site in complex III in generating ROS does not differ between the control and diabetic mitochondria. In conclusion, the mitochondrial ETC is neither the target nor the site of ROS production in kidney tubule mitochondria in short-term diabetes. Mitochondrial fatty acid oxidation is the source of the increased net ROS production, and the site of electron leakage is located proximal to coenzyme Q at the electron transfer flavoprotein that shuttles electrons from acyl-CoA dehydrogenases to coenzyme Q.