Unconventional targeting of a thiol peroxidase to the mitochondrial intermembrane space facilitates oxidative protein folding

Kritsiligkou, P., Chatzi, A., Charalampous, G., Mironov, A., Grant, C. M. and Tokatlidis, K. (2017) Unconventional targeting of a thiol peroxidase to the mitochondrial intermembrane space facilitates oxidative protein folding. Cell Reports, 18(11), pp. 2729-2741. (doi: 10.1016/j.celrep.2017.02.053) (PMID:28297675) (PMCID:PMC5368413)

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Abstract

Thiol peroxidases are conserved hydrogen peroxide scavenging and signaling molecules that contain redox-active cysteine residues. We show here that Gpx3, the major H2O2 sensor 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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Tokatlidis, Professor Kostas and Chatzi, Ms Afroditi
Authors: Kritsiligkou, P., Chatzi, A., Charalampous, G., Mironov, A., Grant, C. M., and Tokatlidis, K.
College/School:College of Medical Veterinary and Life Sciences > Institute of Molecular Cell and Systems Biology
Journal Name:Cell Reports
Publisher:Elsevier (Cell Press)
ISSN:2211-1247
ISSN (Online):2211-1247
Published Online:14 March 2017
Copyright Holders:Copyright © 2017 The Authors
First Published:First published in Cell Reports 18(11):2729-2741
Publisher Policy:Reproduced under a Creative Commons License
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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
624931Oxidative Folding and Redox Signalling in the Mitochondria Intermembrane Space.Konstantinos TokatlidisRoyal Society (ROYSOC)WM120111RI MOLECULAR CELL & SYSTEMS BIOLOGY
459161Scottish Universities Life Sciences Alliance (SULSA)- Enhancing Research Competitiveness Pooling StreamPaul HaganScottish Funding Council (SFC)HR07019SCHOOL OF LIFE SCIENCES
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