Unconventional Targeting of a Thiol Peroxidase to the Mitochondrial Intermembrane Space Facilitates Oxidative Protein Folding

Publication date: 14 March 2017
Source:Cell Reports, Volume 18, Issue 11
Author(s): Paraskevi Kritsiligkou, Afroditi Chatzi, Georgia Charalampous, Aleksandr Mironov, Chris M. Grant, Kostas Tokatlidis
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.

Graphical abstract

Teaser

The redox sensor protein Gpx3 is imported into yeast mitochondria via a targeting sequence encoded from an upstream non-AUG codon. Kritsiligkou et al. show that mitochondrial Gpx3 acts in collaboration with the oxidative protein-folding machinery to ensure mitochondrial proteostasis and morphology.


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