DEFECTS AT CENTER-P UNDERLIE DIABETES-ASSOCIATED MITOCHONDRIAL DYSFUNCTION

Detailed respiration studies on isolated liver mitochondria from strep tozotocin-induced diabetic Sprague-Dawley rats revealed a disease-asso ciated decrease in the ADP/O ratio, a marker for mitochondrial ability to couple the consumption of oxygen to the phosphorylation of ADP. Th is decrease was observed following induction of respiration with gluta mate/malate, succinate, or duroquinol, which enter the electron transp ort chain selectively at complexes I (NADH dehydrogenase), II (succina te dehydrogenase), or III (cytochrome bc1 complex), respectively. Thes e data, coupled with studies using respiratory inhibitors (most import antly antimycin A and myxothiazol), localize at least a portion of thi s defect to a single site within the electron transport chain (center P in the Q-cycle portion of complex III). These results suggest that l iver mitochondria from diabetic animals may generate increased levels of reactive oxygen species at the portion of the electron transport ch ain already established as the major site of mitochondrial free radica l generation. The reduction in the ADP/O ratio occurred in mitochondri a that do not have overt defects in the respiratory control ratio or i n State 3 and State 4 respiration. The data in this paper suggest that defects in center P of the electron transport chain likely increase m itochondrial exposure to oxidants in the diabetic. This data may parti ally explain the evidence of altered exposure and/or response to react ive species in mitochondria from diabetics. This work thus provides fu rther clues to the interaction between oxidative stress and diabetes-a ssociated mitochondrial dysfunction. Copyright (C) 1997 Elsevier Scien ce Inc.