{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,18]],"date-time":"2026-04-18T06:36:37Z","timestamp":1776494197807,"version":"3.51.2"},"reference-count":32,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2024,12,10]],"date-time":"2024-12-10T00:00:00Z","timestamp":1733788800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Fondation de l\u2019Ataxie Charlevoix-Saguenay and BBSRC","award":["BB\/R003335\/1"],"award-info":[{"award-number":["BB\/R003335\/1"]}]},{"name":"Fondation de l\u2019Ataxie Charlevoix-Saguenay and BBSRC","award":["MGU0401"],"award-info":[{"award-number":["MGU0401"]}]},{"name":"Barts Charity","award":["BB\/R003335\/1"],"award-info":[{"award-number":["BB\/R003335\/1"]}]},{"name":"Barts Charity","award":["MGU0401"],"award-info":[{"award-number":["MGU0401"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Mitochondrial dysfunction is implicated in the pathogenesis of the neurological condition autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS), yet precisely how the mitochondrial metabolism is affected is unknown. Thus, to better understand changes in the mitochondrial metabolism caused by loss of the sacsin protein (encoded by the SACS gene, which is mutated in ARSACS), we performed mass spectrometry-based tracer analysis, with both glucose- and glutamine-traced carbon. Comparing the metabolite profiles between wild-type and sacsin-knockout cell lines revealed increased reliance on aerobic glycolysis in sacsin-deficient cells, as evidenced by the increase in lactate and reduction of glucose. Moreover, sacsin knockout cells differentiated towards a neuronal phenotype had increased levels of tricarboxylic acid cycle metabolites relative to the controls. We also observed disruption in the glutaminolysis pathway in differentiated and undifferentiated cells in the absence of sacsin. In conclusion, this work demonstrates consequences for cellular metabolism associated with a loss of sacsin, which may be relevant to ARSACS.<\/jats:p>","DOI":"10.3390\/ijms252413242","type":"journal-article","created":{"date-parts":[[2024,12,10]],"date-time":"2024-12-10T08:40:10Z","timestamp":1733820010000},"page":"13242","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Altered Cellular Metabolism Is a Consequence of Loss of the Ataxia-Linked Protein Sacsin"],"prefix":"10.3390","volume":"25","author":[{"given":"Laura","family":"Perna","sequence":"first","affiliation":[{"name":"William Harvey Research Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6607-4083","authenticated-orcid":false,"given":"Grace","family":"Salsbury","sequence":"additional","affiliation":[{"name":"William Harvey Research Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mohammed","family":"Dushti","sequence":"additional","affiliation":[{"name":"William Harvey Research Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK"},{"name":"Pharmacology & Toxicology Department, Faculty of Medicine, Kuwait University, Kuwait City P.O. Box 24923, Kuwait"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1808-6570","authenticated-orcid":false,"given":"Christopher J.","family":"Smith","sequence":"additional","affiliation":[{"name":"William Harvey Research Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0856-5121","authenticated-orcid":false,"given":"Valle","family":"Morales","sequence":"additional","affiliation":[{"name":"Barts Cancer Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katiuscia","family":"Bianchi","sequence":"additional","affiliation":[{"name":"Barts Cancer Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4914-6794","authenticated-orcid":false,"given":"Gabor","family":"Czibik","sequence":"additional","affiliation":[{"name":"William Harvey Research Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1876-1505","authenticated-orcid":false,"given":"J. Paul","family":"Chapple","sequence":"additional","affiliation":[{"name":"William Harvey Research Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,12,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1038\/72769","article-title":"ARSACS, a spastic ataxia common in northeastern Qu\u00e9bec, is caused by mutations in a new gene encoding an 11.5-kb ORF","volume":"24","author":"Engert","year":"2000","journal-title":"Nat. Genet."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1556","DOI":"10.1093\/hmg\/ddp067","article-title":"The ataxia protein sacsin is a functional co-chaperone that protects against polyglutamine-expanded ataxin-1","volume":"18","author":"Parfitt","year":"2009","journal-title":"Hum. Mol. 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