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Brain mitochondrial metabolism in experimental thiamine deficiency

From the Departments of Neurology and Pediatrics, School of Medicine, The University of Colorado Health Sciences Center, Denver, CO.

Thiamine deficiency causes Wernicke's encephalopathy, although the precise mechanism is unknown. We used a low-thiamine diet in conjunction with a thiamine analog, pyrithiamine, as a model of severe thiamine deficiency in rats. We investigated the function of intact, coupled mitochondria isolated from both brain and liver. State 4 respiration did not change in the thiamine-deficient animals. Brain state 3 rates fell in thiamine-deficient animals when pyruvate/malate, alpha-ketoglutarate, or glutamate were used as substrate. Liver state 3 rates were depressed only when pyruvate/malate was substrate. Activities of brain and liver pyruvate dehydrogenase complex and alpha-ketoglutarate dehydrogenase complex were depressed in the thiamine-deficient group. We conclude that the mitochondrial abnormalities resulting from thiamine deficiency are secondary to depression of thiamine-mediated enzyme activity, rather than from a putative role of thiamine in chemiosmotic coupling, and that the resulting abnormalities in ATP synthesis and perhaps in glutamate catabolism result in the irreversible neurologic defect seen in this disease.

Address correspondence and reprint requests to Dr. Parker, Division of Pediatric Neurology, Box C229, University of Colorado Health Sciences Center, 4200 East Ninth Avenue, Denver, CO 80262.

Supported by a Clinical Research Grant and a postdoctoral research grant from the Muscular Dystrophy Association; NIH Program Project Grant HD08315 and National Research Service Award HD07096, both from NICHD.

Accepted for publication March 13, 1984.