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.
Highlights
We have recently identified mutations in the mitochondrial xprolyl aminopeptidase, XPNPEP3, in families that have a rare autosomal recessive form of renal failure [1]
We found that the rates of mitochondrial oxygen consumption in both strains were comparable when energy production was limited to oxidative phosphorylation by supplying a single non-fermentable carbon substrate in the growth media (Figure 1D)
We have utilized S. cerevisiae as a simple model organism to characterize the phenotype of the icp55 deletion strain and gain insight into the pathogenetic mechanisms that contribute to the progressive kidney disease observed in the setting of XPNPEP3 mutations
Summary
We have recently identified mutations in the mitochondrial xprolyl aminopeptidase, XPNPEP3, in families that have a rare autosomal recessive form of renal failure [1]. Subsequent studies with the S. cerevisiae ortholog, intermediate cleaving peptidase 55 (Icp55p), confirmed that it has an aminopeptidase function, but the presence of proline in the second position of the peptide chain was not invariably required for cleavage of the amino-terminal residue [3,4]. Deletion of icp in S. cerevisiae increases the proteolytic rate of its substrate proteins through a protein degradation pathway characterized by the N-end rule [8,9]. Mdl1p is an ATP-binding cassette (ABC) transporter localized to the inner mitochondrial membrane of S. cerevisiae and has been shown to transport peptide fragments of degraded proteins from the mitochondrial matrix to the cytosol [10]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
