AIF meets the CHCHD4/Mia40-dependent mitochondrial import pathway

Reinhardt, C., Arena, G., Nedara, K., Edwards, R., Brenner, C., Tokatlidis, K. and Modjtahedi, N. (2020) AIF meets the CHCHD4/Mia40-dependent mitochondrial import pathway. Biochimica et Biophysica Acta: Molecular Basis of Disease, 1866(6), 165746. (doi: 10.1016/j.bbadis.2020.165746) (PMID:32105825)

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Abstract

In the mitochondria of healthy cells, Apoptosis-Inducing factor (AIF) is required for the optimal functioning of the respiratory chain machinery, mitochondrial integrity, cell survival, and proliferation. In all analysed species, it was revealed that the downregulation or depletion of AIF provokes mainly the post-transcriptional loss of respiratory chain Complex I protein subunits. Recent progress in the field has revealed that AIF fulfils its mitochondrial pro-survival function by interacting physically and functionally with CHCHD4, the evolutionarily-conserved human homolog of yeast Mia40. The redox-regulated CHCHD4/Mia40-dependent import machinery operates in the intermembrane space of the mitochondrion and controls the import of a set of nuclear-encoded cysteine-motif carrying protein substrates. In addition to their participation in the biogenesis of specific respiratory chain protein subunits, CHCHD4/Mia40 substrates are also implicated in the control of redox regulation, antioxidant response, translation, lipid homeostasis and mitochondrial ultrastructure and dynamics. Here, we discuss recent insights on the AIF/CHCHD4-dependent protein import pathway and review current data concerning the CHCHD4/Mia40 protein substrates in metazoan. Recent findings and the identification of disease-associated mutations in AIF or in specific CHCHD4/Mia40 substrates have highlighted these proteins as potential therapeutic targets in a variety of human disorders.

Item Type:Articles
Additional Information:CR was supported by PhD fellowships from Gustave Roussy course of Excellence in Oncology-Fondation Philanthropia and Fondation pour la recherche contre le cancer (ARC). G.A. was supported by the French National Cancer Institute (INCa 2017-1-PL BIO-08). K.N. received a PhD fellowship from the French Ministry of higher education, research and innovation. N.M. was supported by French National Cancer Institute (INCa 2017-1-PL BIO-08) and Fondation EDF. C.B. was supported by French National Cancer Institute (INCa 2017-1-PL BIO-08). RE was supported by a Lord Kelvin-Adam Smith PhD studentship from the University of Glasgow. K.T. was supported by the UKRI-BBSRC (grant BB/R009031/1), EU COST Action CA15133 (‘FeSBioNet’) and a joint BBSRC-EPSRC Impact Accelerator grant (University of Glasgow).
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Tokatlidis, Professor Kostas and Edwards, Mr Ruairidh
Authors: Reinhardt, C., Arena, G., Nedara, K., Edwards, R., Brenner, C., Tokatlidis, K., and Modjtahedi, N.
College/School:College of Medical Veterinary and Life Sciences > Institute of Molecular Cell and Systems Biology
Journal Name:Biochimica et Biophysica Acta: Molecular Basis of Disease
Publisher:Elsevier
ISSN:0925-4439
ISSN (Online):1879-260X
Published Online:24 February 2020

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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