Respiratory chain cysteine and methionine usage indicate a causal role for thiyl radicals in aging

The identification of longevity-related structural adaptations in biological macromolecules may yield relevant insights into the molecular mechanisms of aging. In screening fully sequenced animal proteomes for signals associated with longevity, it was found that cysteine depletion in respiratory chain complexes was the by far strongest predictor on the amino acid usage level to co-vary with lifespan. This association was though restricted to aerobic animals, whereas anaerobic animals showed variable cysteine accumulation. By contrast, methionine accumulation, a prominent feature of mitochondrially encoded proteins affording competitive antioxidant protection, was not predictive of longevity, but rather paralleled aerobic metabolic capacity. Hence, the easily oxidized sulfur-containing amino acids cysteine (a thiol) and methionine (a thioether) show doubly diametrical behaviour in two central paradigms of respiratory oxidative stress. From this comparison, it is concluded that only the one–electron oxidation of thiols to thiyl radicals contributes to aging, whereas other forms of sulfur oxidation, especially even-electron oxidation of both thiols and thioethers, are less critically involved, presumably as their consequences may be much more easily repaired. Thiyl radicals may yet act as chain-transfer agents to entail an irreversible intramembrane cross-linking (“plastination”) of some of the a priori most hydrophobic and insoluble proteins known, the respiratory chain complexes.

Research Highlights
► Cysteine avoidance in mitochondrially encoded proteins predicts longevity in aerobes.
► Methionine accumulation in these proteins predicts aerobic capacity, but not longevity.
► Thus, a specific facet of cysteine's redox chemistry must be prejudicial to longevity.
► This facet is likely to be the formation of thiyl radicals acting as chain-transfer agents.
► Thiyl radicals may lead to inner mitochondrial membrane plastination.