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Mitochondrial aminopeptidase deletion increases chronological lifespan and oxidative stress resistance while decreasing respiratory metabolism in S. cerevisiae.

ABSTRACT: Recessive mutations in XPNPEP3, encoding a mitochondrial x-prolyl aminopeptidase, have been identified in families with a rare hereditary tubulointerstitial kidney disease. The yeast ortholog of XPNPEP3, Icp55p, participates in the proteolytic processing and stabilization of mitochondrial proteins and its deletion accelerates the degradation of its protein targets. We used icp55 deletion strains of S. cerevisiae to model loss of XPNPEP3 enzymatic function and study its phenotypic consequences on mitochondrial function. We found that Icp55p is not required for respiratory competence; however, compared to controls deletion strains had reduced mitochondrial oxygen consumption when grown in glucose containing media. The reduced mitochondrial respiration of icp55 deletion strains in glucose media requires the mitochondrial peptide transporter, Mdl1p, and was corrected by Tor1p inhibition with rapamycin. Under similar growth conditions the abundance of the mitochondrial ATP synthase complex was decreased in the icp55 deletion strain and was corrected by concurrent deletion of tor1. The icp55 deletion strain demonstrated an increased chronological lifespan and decreased reactive oxygen species. These changes were additive to similar changes known to occur in tor1 deletion strains suggesting independent mechanisms. Together, these results demonstrate that loss of Icp55p function reduces mitochondrial oxygen consumption and ATP synthase complex assembly in glucose media, while also promoting stress resistance, decreasing reactive oxygen species and increasing chronological lifespan through mechanisms that are distinct from decreased Tor1p activity.

SUBMITTER: Stames EM

PROVIDER: S-EPMC3792884 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Mitochondrial aminopeptidase deletion increases chronological lifespan and oxidative stress resistance while decreasing respiratory metabolism in S. cerevisiae.

Stames Erine M EM O'Toole John F JF

PloS one 20131008 10

Recessive mutations in XPNPEP3, encoding a mitochondrial x-prolyl aminopeptidase, have been identified in families with a rare hereditary tubulointerstitial kidney disease. The yeast ortholog of XPNPEP3, Icp55p, participates in the proteolytic processing and stabilization of mitochondrial proteins and its deletion accelerates the degradation of its protein targets. We used icp55 deletion strains of S. cerevisiae to model loss of XPNPEP3 enzymatic function and study its phenotypic consequences on ...[more]

PMID: 24116217

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Project description:We have performed a comprehensive analysis of the involvement of histone H3 and H4 residues in the regulation of chronological lifespan in yeast and identify four structural groups in the nucleosome that influence lifespan. We also identify residues where substitution with an epigenetic mimic extends lifespan, providing evidence that a simple epigenetic switch, without possible additional background modifications, causes longevity. Residues where substitution result in the most pronounced lifespan extension are all on the exposed face of the nucleosome, with the exception of H3E50, which is present on the lateral surface, between two DNA gyres. Other residues that have a more modest effect on lifespan extension are concentrated at the extremities of the H3-H4 dimer, suggesting a role in stabilizing the dimer in its nucleosome frame. Residues that reduce lifespan are buried in the histone handshake motif, suggesting that these mutations destabilize the octamer structure. All residues exposed on the nucleosome disk face and that cause lifespan extension are known to interact with Sir3. We find that substitution of H4K16 and H4H18 cause Sir3 to redistribute from telomeres and silent mating loci to secondary positions, often enriched for Rap1, Abf1 or Reb1 binding sites, whereas H3E50 does not. The redistribution of Sir3 in the genome can be reproduced by an equilibrium model based on primary and secondary binding sites with different affinities for Sir3. The redistributed Sir3 cause transcriptional repression at most of the new loci, including of genes where null mutants were previously shown to extend chronological lifespan. The transcriptomic profiles of H4K16 and H4H18 mutant strains are very similar, and compatible with a DNA replication stress response. This is distinct from the transcriptomic profile of H3E50, which matches strong induction of oxidative phosphorylation. We propose that the different groups of residues are involved in binding to heterochromatin proteins, in destabilizing the association of the nucleosome DNA, disrupting binding of the H3-H4 dimer in the nucleosome, or disrupting the structural stability of the octamer, each category impacting on chronological lifespan by a different mechanism.

Dataset Information

Mitochondrial aminopeptidase deletion increases chronological lifespan and oxidative stress resistance while decreasing respiratory metabolism in S. cerevisiae.

Publications

Mitochondrial aminopeptidase deletion increases chronological lifespan and oxidative stress resistance while decreasing respiratory metabolism in S. cerevisiae.

Similar Datasets

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