Enhanced ROS Production in Mitochondria from Prematurely Aging mtDNA Mutator Mice

AbstractAn increase in mitochondrial DNA (mtDNA) mutations and an ensuing increase in mitochondrial reactive oxygen species (ROS) production have been suggested to be a cause of the aging process ( “the mitochondrial hypothesis of aging”). In agreement with this, mtDNA-mutator mice accumulate a large amount of mtDNA mutations, giving rise to defective mitochondria and an accelerated aging phenotype. However, incongruously, the rates of ROS production in mtDNA mutator mitochondria have gene rally earlier been reported to be lower – not higher – than in wildtype, thus apparently invalidating the “mitochondrial hypothesis of aging”. We have here re-examined ROS production rates in mtDNA-mutator mice mitochondria. Using traditional conditions for measuring ROS (succinate in the absence of rotenone), we indeed found lower ROS in the mtDNA-mutator mitochondria compared to wildtype. This ROS mainly results from reverse electron flow driven by the membrane potential, but the membrane potential reached in the isolated mtDNA-mutator mitochondria was 33 mV lower than that in wil dtype mitochondria, due to the feedback inhibition of succinate oxidation by oxaloacetate, and to a lower oxidative capacity in the mtDNA-mutator mice, explaining the lower ROS production. In contrast, in normal forward electron flow systems (pyruvate (or glutamate) + malate or palmitoyl-CoA + c arnitine), mitochondrial ROS production was higher in the mtDNA-mutator mitochondria. Particularly,...
Source: Biochemistry (Moscow) - Category: Biochemistry Source Type: research