The Mia40/CHCHD4 oxidative folding system: Redox regulation and signaling in the mitochondrial intermembrane space

Dickson-Murray, E., Nedara, K., Modjtahedi, N. and Tokatlidis, K. (2021) The Mia40/CHCHD4 oxidative folding system: Redox regulation and signaling in the mitochondrial intermembrane space. Antioxidants, 10(4), 592. (doi: 10.3390/antiox10040592) (PMID:33921425) (PMCID:PMC8069373)

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Abstract

Mitochondria are critical for several cellular functions as they control metabolism, cell physiology, and cell death. The mitochondrial proteome consists of around 1500 proteins, the vast majority of which (about 99% of them) are encoded by nuclear genes, with only 13 polypeptides in human cells encoded by mitochondrial DNA. Therefore, it is critical for all the mitochondrial proteins that are nuclear-encoded to be targeted precisely and sorted specifically to their site of action inside mitochondria. These processes of targeting and sorting are catalysed by protein translocases that operate in each one of the mitochondrial sub-compartments. The main protein import pathway for the intermembrane space (IMS) recognises proteins that are cysteine-rich, and it is the only import pathway that chemically modifies the imported precursors by introducing disulphide bonds to them. In this manner, the precursors are trapped in the IMS in a folded state. The key component of this pathway is Mia40 (called CHCHD4 in human cells), which itself contains cysteine motifs and is subject to redox regulation. In this review, we detail the basic components of the MIA pathway and the disulphide relay mechanism that underpins the electron transfer reaction along the oxidative folding mechanism. Then, we discuss the key protein modulators of this pathway and how they are interlinked to the small redox-active molecules that critically affect the redox state in the IMS. We present also evidence that the mitochondrial redox processes that are linked to iron–sulfur clusters biogenesis and calcium homeostasis coalesce in the IMS at the MIA machinery. The fact that the MIA machinery and several of its interactors and substrates are linked to a variety of common human diseases connected to mitochondrial dysfunction highlight the potential of redox processes in the IMS as a promising new target for developing new treatments for some of the most complex and devastating human diseases.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Dickson-Murray, Eleanor and Tokatlidis, Professor Kostas
Creator Roles:
Dickson-Murray, E.Writing – original draft, Writing – review and editing
Tokatlidis, K.Conceptualization, Writing – review and editing, Supervision, Project administration, Funding acquisition
Authors: Dickson-Murray, E., Nedara, K., Modjtahedi, N., and Tokatlidis, K.
College/School:College of Medical Veterinary and Life Sciences > School of Molecular Biosciences
Journal Name:Antioxidants
Publisher:MDPI
ISSN:2076-3921
ISSN (Online):2076-3921
Published Online:12 April 2021
Copyright Holders:Copyright © 2021 by the authors
First Published:First published in Antioxidants
Publisher Policy:Reproduced under a Creative Commons license

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
300402Mitochondria salvage via a novel antioxidant protein import pathwayKonstantinos TokatlidisBiotechnology and Biological Sciences Research Council (BBSRC)BB/R009031/1Institute of Molecular, Cell & Systems Biology
306567Mitochondrial ROS mapping and control with sub-organellar resolutionKonstantinos TokatlidisBiotechnology and Biological Sciences Research Council (BBSRC)BB/T003804/1Institute of Molecular, Cell & Systems Biology