title: Unconventional Targeting of a Thiol Peroxidase to the Mitochondrial Intermembrane Space Facilitates Oxidative Protein Folding.
abstract: Thiol peroxidases are conserved hydrogen peroxide scavenging and signaling molecules that contain redox-active cysteine residues. We show here that Gpx3, the major H2O2sensor in yeast, is present in the mitochondrial intermembrane space (IMS), where it serves a compartment-specific role in oxidative metabolism. The IMS-localized Gpx3 contains an 18-amino acid N-terminally extended form encoded from a non-AUG codon. This acts as a mitochondrial targeting signal in a pathway independent of the hitherto known IMS-import pathways. Mitochondrial Gpx3 interacts with the Mia40 oxidoreductase in a redox-dependent manner and promotes efficient Mia40-dependent oxidative protein folding. We show that cells lacking Gpx3 have aberrant mitochondrial morphology, defective protein import capacity, and lower inner membrane potential, all of which can be rescued by expression of a mitochondrial-only form of Gpx3. Together, our data reveal a novel role for Gpx3 in mitochondrial redox regulation and protein homeostasis.
authors.affiliation: Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PL, UK.
authors.forename: Paraskevi
authors.initials: P
authors.lastname: Kritsiligkou
authors.affiliation: Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK.
authors.forename: Afroditi
authors.initials: A
authors.lastname: Chatzi
authors.affiliation: Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK.
authors.forename: Georgia
authors.initials: G
authors.lastname: Charalampous
authors.affiliation: Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PL, UK.
authors.forename: Aleksandr
authors.initials: A
authors.lastname: Mironov
authors.affiliation: Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PL, UK. Electronic address: chris.grant@manchester.ac.uk.
authors.forename: Chris M
authors.initials: CM
authors.lastname: Grant
authors.affiliation: Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK. Electronic address: kostas.tokatlidis@glasgow.ac.uk.
authors.forename: Kostas
authors.initials: K
authors.lastname: Tokatlidis
mesh_terms: D000595:Amino Acid Sequence; D003062:Codon / Q000235:genetics; D017353:Gene Deletion; D005979:Glutathione Peroxidase / Q000737:chemistry / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism / Q000648:ultrastructure; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000201:enzymology* / Q000648:ultrastructure; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D008954:Models, Biological; D010084:Oxidation-Reduction; D010641:Phenotype; D011485:Protein Binding; D017510:Protein Folding; D012441:Saccharomyces cerevisiae / Q000201:enzymology*; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry / Q000378:metabolism*
chemical_list: D003062:Codon; C495320:MIA40 protein, S cerevisiae; D033681:Mitochondrial Membrane Transport Proteins; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D029701:Saccharomyces cerevisiae Proteins; D005979:Glutathione Peroxidase; C494438:HYR1 protein, S cerevisiae
keywords: Gpx3; Mia40; alternative translation initiation; antioxidants; mitochondria; mitochondria biogenesis; oxidative protein folding; oxidative stress; protein targeting