Depletion of mitochondrial DNA alters glucose metabolism in SK-Hep1 cells

Maternally inherited mitochondrial DNA (mtDNA) has been suggested to be a g enetic factor for diabetes. Reports have shown a decrease of mtDNA content in tissues of diabetic patients. We investigated the effects of mtDNA deple tion on glucose metabolism by use of rho (0) SK-Hep1 human hepatoma cells, whose mtDNA was depleted by long-term exposure to ethidium bromide. The rho (0) cells failed to hyperpolarize mitochondrial membrane potential in resp onse to glucose stimulation. Intracellular ATP content, glucose-stimulated ATP production, glucose uptake, steady-state mRNA and protein levels of glu cose transporters, and cellular activities of glucose-metabolizing enzymes were decreased in rho (0) cells compared with parental rho (+) cells. Our r esults suggest that the quantitative reduction of mtDNA may suppress the ex pression of nuclear DNA-encoded glucose transporters and enzymes of glucose metabolism. Thus this may lead to diabetic status, such as decreased ATP p roduction and glucose utilization.