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.