Mitochondrial disease in mouse results in increased oxidative stress

It has been hypothesized that a major factor in the progression of mitochon drial disease resulting from defects in oxidative phosphorylation (OXPHOS) is the stimulation of the mitochondrial production of reactive oxygen speci es (ROS) and the resulting damage to the mtDNA. To test this hypothesis, we examined the mitochondria from mice lacking the heart/muscle isoform of th e adenine nucleotide translocator (Ant1), designated An1(tm2Mgr) (-/-) mice . The absence of Anti blocks the exchange of ADP and ATP across the mitocho ndrial inner membrane, thus inhibiting OXPHOS, Consistent with Anti express ion, mitochondria isolated from skeletal muscle, heart, and brain of the An t1-deficient mice produced markedly increased amounts of the ROS hydrogen p eroxide, whereas liver mitochondria, which express a different Ant isoform, produced normally low levels of hydrogen peroxide, The increased productio n of ROS by the skeletal muscle and heart was associated with a dramatic in crease in the ROS detoxification enzyme manganese superoxide dismutase (Sod 2, also known as MnSod) in muscle tissue and muscle mitochondria, a modest increase in Sod2 in heart tissue, and no increase in heart mitochondria, Th e level of glutathione peroxidase-1 (Gpx1), a second ROS detoxifying enzyme , was increased moderately in the mitochondria of both tissues. Consistent with the lower antioxidant defenses in heart, the heart mtDNAs of the Ant1- deficient mice showed a striking increase in the accumulation of mtDNA rear rangements, whereas skeletal muscle, with higher antioxidant defenses, had fewer mtDNA rearrangements. Hence, inhibition of OXPHOS does increase mitoc hondrial ROS production, eliciting antioxidant defenses, If the antioxidant defenses are insufficient to detoxify the ROS, then an increased mtDNA mut ation rate can result.