The mitochondrial protein Sideroflexin 3 (SFXN3) influences neurodegeneration pathways in vivo

Ledahawsky, L. M. et al. (2022) The mitochondrial protein Sideroflexin 3 (SFXN3) influences neurodegeneration pathways in vivo. FEBS Journal, 289(13), pp. 3894-3914. (doi: 10.1111/febs.16377) (PMID:35092170) (PMCID:PMC9542548)

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Abstract

Synapses are a primary pathological target in neurodegenerative diseases. Identifying therapeutic targets at the synapse could delay progression of numerous conditions. The mitochondrial protein SFXN3 is a neuronally-enriched protein expressed in synaptic terminals and regulated by key synaptic proteins, including α-synuclein. We first show that SFXN3 uses the carrier import pathway to insert into the inner mitochondrial membrane. Using high-resolution proteomics on Sfxn3-KO mice synapses, we then demonstrate that SFXN3 influences proteins and pathways associated with neurodegeneration and cell death (including CSPα and Caspase-3), as well as neurological conditions (including Parkinson’s disease and Alzheimer’s disease). Over-expression of SFXN3 orthologues in Drosophila models of Parkinson’s Disease significantly reduced dopaminergic neuron loss. In contrast, the loss of SFXN3 was insufficient to trigger neurodegeneration in mice, indicating an anti- rather than pro-neurodegeneration role for SFXN3. Taken together, these results suggest a potential role for SFXN3 in the regulation of neurodegeneration pathways.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Tokatlidis, Professor Kostas and Edwards, Mr Ruairidh and Terzenidou, Dr Maria Eirini
Authors: Ledahawsky, L. M., Terzenidou, M. E., Edwards, R., Kline, R. A., Graham, L. C., Eaton, S. L., van der Hoorn, D., Chaytow, H., Huang, Y.‐T., Groen, E. J.N., Motyl, A. A. L., Lamont, D. J., Tokatlidis, K., Wishart, T. M., and Gillingwater, T. H.
College/School:College of Medical Veterinary and Life Sciences > School of Molecular Biosciences
Journal Name:FEBS Journal
Publisher:Wiley
ISSN:1742-464X
ISSN (Online):1742-4658
Published Online:28 January 2022
Copyright Holders:Copyright © 2022 The Authors
First Published:First published289(13): 3894-3914
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
168087Oxidative Folding and Redox Signalling in the Mitochondria Intermembrane Space.Konstantinos TokatlidisThe Royal Society (ROYSOC)WM120111Institute of Molecular, Cell & Systems Biology
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