Abstract
The mitochondrial hypothesis on aging suggests stochastic stomatic mutations of mitochondrial DNA (mtDNA) as an important cause of respiratory-defective cells and the decline of energetic capabilities with increasing age. Reactive oxygen species (ROS), which are produced in the respiratory chain under stress conditions, are assumed to cause deletions and/or mutations of mtDNA. Using quantitative PCR, the stochastic distribution of the "common deletion" of mtDNA in human skeletal muscle tissue is shown. Recent data suggest that in vivo, under normal conditions, respiration is controlled by the intramitochondrial ATP/ADP ratio, via interaction of the nucleotides with subunit IV of cytochrome c oxidase, representing the rate-limiting step of the respiratory chain. Kinetic data are presented indicating that this "second mechanism of respiratory control" is turned on by cAMP-dependent phosphorylation of the enzyme and turned off by mitochondrial protein phosphatases. It is proposed that dephosphorylation of cytochrome c oxidase via "deleterious stress signals" results in increased mitochondrial membrane potentials and stimulated production of ROS in the mitochondrial respiratory chain. As a consequence, mutations of mtDNA would increase and aging would be accelerated. The inhibition of cytochrome c oxidase at high ATP/ADP ratios can also be abolished by low concentrations of free palmitate and high substrate pressure in the respiratory chain, supporting the notion that low caloric diet supports longevity.
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