Diabetes-prone BHE/Cdb and Sprague-Dawley (SD) rats were studied with respect to mitochondrial (mt) function and mt gene expression. The BHE/Cdb rats carry mutations in the mt ATPase 6 gene that phenotype as decreased OXPHOS efficiency with subsequent development of impaired glucose tolerance. The base substitutions result in amino acid substitutions in the proton channel and this, in turn, affects the efficiency of energy capture in the ATP molecule. Feeding studies showed that BHE/Cdb rats required 10 times more vitamin E and three times more vitamin A in their diets than do normal SD rats. Vitamin A supplementation 'normalized' mt OXPHOS as well as increased the amount of ATPase subunit a protein in the mt compartment. Western blot analysis of retinoic acid receptors in the mitochondrial and nuclear compartments showed that these proteins were present in the mt compartment. The effect of the vitamin A supplementation plus the observation of retinoic acid receptors suggest that vitamin A functions to enhance the transcription of the ATPase 6 gene. Work with primary cultures of hepatocytes showed that not only does retinoic acid increase mitochondrial ATPase 6 gene expression but so too does the steroid hormone intermediate, dehydroepiandrosterone (DHEA). Triiodothyronine also plays a role in this process but not as an independent factor. Rather, this hormone potentiates the effects of retinoic acid and DHEA on ATPase gene expression. These results suggest that mt gene expression requires more than just the mt transcription factor A. More than likely the process requires a number of factors in much the same way as does nuclear gene expression.