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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 \u03b1\u2010synuclein. We first show that SFXN3 uses the carrier import pathway to insert into the inner mitochondrial membrane. Using high\u2010resolution proteomics on\n                    <jats:italic>Sfxn3<\/jats:italic>\n                    \u2010KO mice synapses, we then demonstrate that SFXN3 influences proteins and pathways associated with neurodegeneration and cell death (including CSP\u03b1 and Caspase\u20103), as well as neurological conditions (including Parkinson's disease and Alzheimer\u2019s disease). Overexpression of SFXN3 orthologues in\n                    <jats:italic>Drosophila<\/jats:italic>\n                    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\u2010 rather than pro\u2010neurodegeneration role for SFXN3. Taken together, these results suggest a potential role for SFXN3 in the regulation of neurodegeneration pathways.\n                  <\/jats:p>","DOI":"10.1111\/febs.16377","type":"journal-article","created":{"date-parts":[[2022,1,28]],"date-time":"2022-01-28T20:00:55Z","timestamp":1643400055000},"page":"3894-3914","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["The mitochondrial protein Sideroflexin 3 (SFXN3) influences neurodegeneration pathways\n                    <i>in\u00a0vivo<\/i>"],"prefix":"10.1111","volume":"289","author":[{"given":"Leire M.","family":"Ledahawsky","sequence":"first","affiliation":[{"name":"Edinburgh Medical School Biomedical Sciences University of Edinburgh UK"},{"name":"Euan MacDonald Centre for Motor Neuron Disease Research University of Edinburgh UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Eirini","family":"Terzenidou","sequence":"additional","affiliation":[{"name":"Institute of Molecular Cell and Systems Biology College of Medical, Veterinary and Life Sciences University of Glasgow UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruairidh","family":"Edwards","sequence":"additional","affiliation":[{"name":"Institute of Molecular Cell and Systems Biology College of Medical, Veterinary and Life Sciences University of Glasgow UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel A.","family":"Kline","sequence":"additional","affiliation":[{"name":"Euan MacDonald Centre for Motor Neuron Disease Research University of Edinburgh UK"},{"name":"The Roslin Institute and R(D)SVS University of Edinburgh UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura C.","family":"Graham","sequence":"additional","affiliation":[{"name":"Euan MacDonald Centre for Motor Neuron Disease Research University of Edinburgh UK"},{"name":"The Roslin Institute and R(D)SVS University of Edinburgh UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samantha L.","family":"Eaton","sequence":"additional","affiliation":[{"name":"Euan MacDonald Centre for Motor Neuron Disease Research University of Edinburgh UK"},{"name":"The Roslin Institute and R(D)SVS University of Edinburgh UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dinja","family":"van der Hoorn","sequence":"additional","affiliation":[{"name":"Edinburgh Medical School Biomedical Sciences University of Edinburgh UK"},{"name":"Euan MacDonald Centre for Motor Neuron Disease Research University of Edinburgh UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helena","family":"Chaytow","sequence":"additional","affiliation":[{"name":"Edinburgh Medical School Biomedical Sciences University of Edinburgh UK"},{"name":"Euan MacDonald Centre for Motor Neuron Disease Research University of Edinburgh UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu\u2010Ting","family":"Huang","sequence":"additional","affiliation":[{"name":"Edinburgh Medical School Biomedical Sciences University of Edinburgh UK"},{"name":"Euan MacDonald Centre for Motor Neuron Disease Research University of Edinburgh UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2330-9444","authenticated-orcid":false,"given":"Ewout J. 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