Purine catabolism: Links to mitochondrial respiration and antioxidant defenses?

Type I diabetes in rodents is associated with a spectrum of liver mitochond rial abnormalities ranging from. evidence of oxidative stress and altered a ntioxidant defenses to frank defects in respiration rates and respiratory c ontrol ratios. To better address the myriad changes in redox metabolism in these mitochondria, we have applied new chromatographic techniques that ena ble simultaneous analysis of multiple components of pathways of interest (e .g., purine catabolites and oxidation by-products), We report here a portio n of these results, which, in conjunction with other reported data, suggest that purine catabolism may contribute to mitochondrial antioxidant defense s by producing the antioxidant urate. In liver mitochondria from diabetic r ats, increases in uric acid (threefold) and its direct precursor xanthine ( sixfold) were observed ia moderate diabetes, but levels fell essentially to normal in severe disease. Failure to maintain elevated xanthine and uric a cid occurred contemporaneously with progressive mitochondrial dysfunction. Regression analysis revealed altered precursor-product relationships betwee n,xanthine, its precursors, and uric acid, An independent set of studies in isolated rat liver mitochondria showed that mitochondrial respiration was associated with essentially uniform decreases (similar to 30%) in all purin e catabolites measured (urate, xanthine, hypoxanthine, guanine, guanosine, and xanthosine), That result suggests the potential for, steady production of urate, Taken together, the two studies raise the possibility that purine catabolism may be a previously unappreciated component of the homeostatic response of mitochondria to oxidant stress and may play a critical role in slowing progressive mitochondrial dysfunction in certain disease states. (C ) 1999 Academic Press.