{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T12:13:54Z","timestamp":1791288834338,"version":"4.3.0"},"reference-count":74,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2025,3,28]],"date-time":"2025-03-28T00:00:00Z","timestamp":1743120000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"MUR (Ministero dell\u2019Universit\u00e0 e della Ricerca)","award":["PRIN2022 PNRR N. P2022FBZXY"],"award-info":[{"award-number":["PRIN2022 PNRR N. P2022FBZXY"]}]},{"name":"MUR (Ministero dell\u2019Universit\u00e0 e della Ricerca)","award":["D.M. n. 737 of 25.06.2021"],"award-info":[{"award-number":["D.M. n. 737 of 25.06.2021"]}]},{"name":"MUR (Ministero dell\u2019Universit\u00e0 e della Ricerca)","award":["PRIN2022 N. 2022XTM2S3"],"award-info":[{"award-number":["PRIN2022 N. 2022XTM2S3"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease caused by the degeneration of upper and lower motor neurons in the brain, brainstem and spinal cord. About 10% of familial ALS cases are linked to pathogenetic substitution in TARDBP, the gene encoding the TDP-43 protein. A novel rare causative variant in TARDBP (p.G376D) was recently reported in ALS patients. It leads to TDP-43 cytoplasmic mislocalization, increased oxidative stress and reduced cell viability. However, functional studies on the effects of this molecular defect have not yet been carried out. Mitochondria are highly dynamic organelles, and their deregulation has emerged as a key factor in many diseases, among which is ALS. Therefore, this study aimed at determining the impact of this causative variant on mitochondria. In cellular models expressing TDP-43G376D and in fibroblasts derived from patients carrying this molecular defect, we observed alterations of mitochondrial functionality. We demonstrated increased localization of the mutated protein to mitochondria and a reduced abundance of subunits of complex I and complex II of the mitochondrial respiratory chain, associated with a decrease in mitochondrial membrane potential, in cellular respiration and in cytochrome C oxidase (COX) activity. Moreover, ALS cells showed increased mitochondrial fragmentation and reduced abundance of antioxidant enzymes causing increased oxidative stress. These results expand our knowledge about the molecular mechanisms underlying ALS pathogenesis associated with TDP-43 p.G376D and could help to identify new therapeutic strategies to counteract this disease.<\/jats:p>","DOI":"10.3390\/antiox14040401","type":"journal-article","created":{"date-parts":[[2025,3,28]],"date-time":"2025-03-28T04:36:48Z","timestamp":1743136608000},"page":"401","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Dysfunctional Mitochondria Characterize Amyotrophic Lateral Sclerosis Patients\u2019 Cells Carrying the p.G376D TARDBP Pathogenetic Substitution"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-5470-0354","authenticated-orcid":false,"given":"Giuseppe","family":"Petito","sequence":"first","affiliation":[{"name":"Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania \u201cLuigi Vanvitelli\u201d, 81100 Caserta, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6768-5943","authenticated-orcid":false,"given":"Victoria Stefania","family":"Del Fiore","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine (DiMeS), University of Salento, Via Provinciale Lecce-Monteroni n.165, 73100 Lecce, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arianna","family":"Cuomo","sequence":"additional","affiliation":[{"name":"Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania \u201cLuigi Vanvitelli\u201d, 81100 Caserta, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federica","family":"Cioffi","sequence":"additional","affiliation":[{"name":"Department of Sciences and Technologies, University of Sannio, 82100 Benevento, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5884-9208","authenticated-orcid":false,"given":"Gilda","family":"Cobellis","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, University of Campania \u201cLuigi Vanvitelli\u201d, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5797-0348","authenticated-orcid":false,"given":"Antonia","family":"Lanni","sequence":"additional","affiliation":[{"name":"Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania \u201cLuigi Vanvitelli\u201d, 81100 Caserta, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3379-7469","authenticated-orcid":false,"given":"Flora","family":"Guerra","sequence":"additional","affiliation":[{"name":"Department of Biological and Environmental Sciences and Technologies (DiSTeBA), University of Salento, Via Provinciale Lecce-Monteroni n.165, 73100 Lecce, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6232-6183","authenticated-orcid":false,"given":"Cecilia","family":"Bucci","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine (DiMeS), University of Salento, Via Provinciale Lecce-Monteroni n.165, 73100 Lecce, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1571-0980","authenticated-orcid":false,"given":"Rosalba","family":"Senese","sequence":"additional","affiliation":[{"name":"Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania \u201cLuigi Vanvitelli\u201d, 81100 Caserta, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4987-3561","authenticated-orcid":false,"given":"Roberta","family":"Romano","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine (DiMeS), University of Salento, Via Provinciale Lecce-Monteroni n.165, 73100 Lecce, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,3,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Ragagnin, A.M.G., Shadfar, S., Vidal, M., Jamali, M.S., and Atkin, J.D. 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