(16) SELECTIVE INHIBITION OF ATP SYNTHESIS IN RETINAL MITOCHONDRIA BY FORMIC ACID

Janis T. Eells, Michele M. Henry and Shane N. Milligan
Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI 53226

Formic acid, the toxic metabolite in methanol poisoning, has been hypthesized to produce retinal and optic nerve toxicity by disruption of mitochondrial energy production. Previous studies in our laboratory have documented formate-induced retinal dysfunction, depletion of retinal ATP and mitochondrial disruption in a rodent model of methanol intoxication (Eells, 1991; Eells et al., 1996). The present investigation compared the effect of formate on ATP production in intact mitochondria isolated from two highly aerobic tissues with apparent differences in formate-sensitivity, retina and heart. formate selectively inhibited ATP synthesis in mitochondria isolated from bovine retina in the presence of metabolic substrates supplying electrons at the level of complex I, complex II and complex IV in the electron transport chain. The inhibitory effect of formate on retinal mitochondrial ATP synthesis was concentration-dependent with significant reductions in ATP synthesis produced at 10 mM formate and Ki values ranging from 30 to 50 mM formate. Comparative studies conducted in mitochondria isolated from bovine heart showed little or no inhibition of ATP synthesis at formate concentrations up to 50 mM. These findings provide direct evidence that formate acts as a retinal mitochondrial toxin and suggest that one component of the retinotoxic actions of formate may be due to tissue- or cell-specific differences in mitochondrial transport mechanisms or mitochondrial metabolism. (Supported by NIH grants ES06648, EY01931 and EY11396).