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

1 Division of Metabolic Disease, Department of Biomedical Sciences, National Institute of Health, Seoul 122-701; and Departments of 2 Nuclear Medicine and 3 Internal Medicine, School of Medicine, Seoul National University, Seoul 110-744, Korea Maternally inherited mitochondrial DNA (mtDNA) has been suggested to be a genetic factor for diabetes. Reports have shown a decrease of mtDNA content in tissues of diabetic patients. We investigated the effects of mtDNA depletion on glucose metabolism by use of 0 SK-Hep1 human hepatoma cells, whose mtDNA was depleted by long-term exposure to ethidium bromide. The 0 cells failed to hyperpolarize mitochondrial membrane potential in response to glucose stimulation. Intracellular ATP content, glucose-stimulated ATP production, glucose uptake, steady-state mRNA and protein levels of glucose transporters, and cellular activities of glucose-metabolizing enzymes were decreased in 0 cells compared with parental + cells. Our results suggest that the quantitative reduction of mtDNA may suppress the expression of nuclear DNA-encoded glucose transporters and enzymes of glucose metabolism. Thus this may lead to diabetic status, such as decreased ATP production and glucose utilization. oxidative phosphorylation; glucose uptake