Mitochondrially encoded methionine is inversely related to longevity in mammals

Abstract

SummaryMethionine residues in proteins react readily with reactive oxygen species making them particularly sensitive to oxidation. However, because oxidized methionine can be reduced back in a catalyzed reaction, it has been suggested that methionine residues act as oxidant scavengers, protecting not only the proteins where they are located but also the surrounding macromolecules. To investigate whether methionine residues may be selected for or against animal longevity, we carried out a metaexamination of mitochondrial genomes from mammalian species. Our analyses unveiled a hitherto unnoticed observation: mitochondrially encoded polypeptides from short-lived species are enriched in methionine when compared with their long-lived counterparts. We show evidence suggesting that methionine addition to proteins in short-lived species, rather than methionine loss from proteins in long-lived species, is behind the reported difference in methionine usage. The inverse association between longevity and methionine, which persisted after correction for body mass and phylogenetic interdependence, was paralleled by the methionine codon AUA, but not by the codon AUG. Although nuclear encoded mitochondrial polypeptides exhibited higher methionine usage than nonmitochondrial proteins, correlation with longevity was only found within the group of those polypeptides located in the inner mitochondrial membrane.Based on these results, we propose that short-lived animals subjected to higher oxidative stress selectively accumulate methionine in their mitochondrially encoded proteins, which supports the role of oxidative damage in aging.

Accelerated protein evolution analysis reveals genes and pathways associated with the evolution of mammalian longevity

“…This provides researchers the opportunity of performing genome-wide comparative studies across a large number of species to identify genes and processes associated with the evolution of longevity (Austad 2005;Jobson et al 2010). For example, some studies have employed mitochondrial genomic sequences from multiple species to associate features of mitochondrial proteins with longevity, such as methionine composition (Aledo et al 2011). With the growing number of sequenced genomes, however, these studies have only scratched the surface.…”

Mutational Bias Plays an Important Role in Shaping Longevity-Related Amino Acid Content in Mammalian mtDNA-Encoded Proteins

“…and methionine are particularly sensitive to oxidation (Berlett and Stadtman 1997). Interestingly, mitochondrially encoded cysteine and methionine have both been correlated negatively with longevity (Moosmann and Behl 2008;Aledo et al 2011). Even though both cysteine and methionine are negatively related to longevity, it may be that cysteine is a pro-oxidant while methionine is an anti-oxidant, as we have previously argued (Aledo et al 2011).…”

“…Interestingly, mitochondrially encoded cysteine and methionine have both been correlated negatively with longevity (Moosmann and Behl 2008;Aledo et al 2011). Even though both cysteine and methionine are negatively related to longevity, it may be that cysteine is a pro-oxidant while methionine is an anti-oxidant, as we have previously argued (Aledo et al 2011). In brief, it is the detrimental capacity of cysteine thiyl radicals and their potential to initiate irreversible protein crosslinking that might have caused a selection against cysteine in mtDNA-encoded proteins.…”

“…This point is well illustrated by the finding that the mitochondrial membrane peroxidizability index is inversely related to maximum life span in mammals (Pamplona et al 1998). Along the same lines, different authors have suggested that concerted changes in mtDNA-encoded proteins leading to mitochondrial proteomes better endowed to resist oxidative stress may have evolved in response to selective pressures (Moosmann and Behl 2008;Kitazoe et al 2008;Aledo et al 2011).…”

“…In this way, one equivalent of ROS is destroyed for every equivalent of methionine residue repaired (Levine et al 1996). As such, a methionine enrichment of mitochondrial proteins may represent an adaptive response to oxidative stress (Bender et al 2008;Aledo et al 2011). Therefore, those animals that exhibit higher rates of ROS generation (shortlived animals) might have been subjected to higher selective pressures to increase the methionine content of their mitochondrial proteins.…”