{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:09:45Z","timestamp":1760058585408,"version":"build-2065373602"},"reference-count":37,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2025,4,12]],"date-time":"2025-04-12T00:00:00Z","timestamp":1744416000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Italian Ministry of Health","award":["RC 10\/24","RC 13\/24","RC 36\/25","5M19_5","2022A4CFKH"],"award-info":[{"award-number":["RC 10\/24","RC 13\/24","RC 36\/25","5M19_5","2022A4CFKH"]}]},{"name":"European Union\u2014Next Generation EU\u2014Mission 4","award":["RC 10\/24","RC 13\/24","RC 36\/25","5M19_5","2022A4CFKH"],"award-info":[{"award-number":["RC 10\/24","RC 13\/24","RC 36\/25","5M19_5","2022A4CFKH"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The BCS1L gene encodes a mitochondrial chaperone which inserts the Fe2S2 iron\u2013sulfur Rieske protein into the nascent electron transfer complex III. Variants in the BCS1L gene are associated with a spectrum of mitochondrial disorders, ranging from mild to severe phenotypes. Bj\u00f6rnstad syndrome, a milder condition, is characterized by sensorineural hearing loss (SNHL) and pili torti. More severe disorders include Complex III Deficiency, which leads to neuromuscular and metabolic dysfunctions with multi-systemic issues and Growth Retardation, Aminoaciduria, Cholestasis, Iron Overload, and Lactic Acidosis syndrome (GRACILE). The severity of these conditions varies depending on the specific BCS1L mutation and its impact on mitochondrial function. This study describes a 27-month-old child with SNHL, proximal renal tubular acidosis, woolly hypopigmented hair, developmental delay, and metabolic alterations. Genetic analysis revealed a homozygous BCS1L variant (c.38A&gt;G, p.Asn13Ser), previously reported in a patient with a more severe phenotype that, however, was not functionally characterized. In this work, functional studies in a yeast model and patient-derived fibroblasts demonstrated that the variant impairs mitochondrial respiration, complex III activity (CIII), and also alters mitochondrial morphology in affected fibroblasts. Interestingly, we unveil a new possible mechanism of pathogenicity for BCS1L mutant protein. Since the interaction between BCS1L and CIII is increased, this suggests the formation of a BCS1L-containing nonfunctional preCIII unable to load RISP protein and complete CIII assembly. These findings support the pathogenicity of the BCS1L c.38A&gt;G variant, suggesting altered interaction between the mutant BCS1L and CIII.<\/jats:p>","DOI":"10.3390\/ijms26083670","type":"journal-article","created":{"date-parts":[[2025,4,14]],"date-time":"2025-04-14T06:18:36Z","timestamp":1744611516000},"page":"3670","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Uncovering a Novel Pathogenic Mechanism of BCS1L in Mitochondrial Disorders: Insights from Functional Studies on the c.38A&gt;G Variant"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0110-5942","authenticated-orcid":false,"given":"Valeria","family":"Capaci","sequence":"first","affiliation":[{"name":"Institute for Maternal and Child Health IRCCS Burlo Garofolo, 34137 Trieste, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5886-9129","authenticated-orcid":false,"given":"Luisa","family":"Zupin","sequence":"additional","affiliation":[{"name":"Institute for Maternal and Child Health IRCCS Burlo Garofolo, 34137 Trieste, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5864-5819","authenticated-orcid":false,"given":"Martina","family":"Magistrati","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, 43124 Parma, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8024-0482","authenticated-orcid":false,"given":"Maria Teresa","family":"Bonati","sequence":"additional","affiliation":[{"name":"Institute for Maternal and Child Health IRCCS Burlo Garofolo, 34137 Trieste, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9760-8463","authenticated-orcid":false,"given":"Fulvio","family":"Celsi","sequence":"additional","affiliation":[{"name":"Institute for Maternal and Child Health IRCCS Burlo Garofolo, 34137 Trieste, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Irene","family":"Marrone","sequence":"additional","affiliation":[{"name":"Department of Life Science, University of Trieste, 34127 Trieste, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7523-3154","authenticated-orcid":false,"given":"Francesco","family":"Baldo","sequence":"additional","affiliation":[{"name":"Institute for Maternal and Child Health IRCCS Burlo Garofolo, 34137 Trieste, Italy"},{"name":"Department of Medicine, Surgery and Health Sciences, University of Trieste, 34129 Trieste, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Blendi","family":"Ura","sequence":"additional","affiliation":[{"name":"Institute for Maternal and Child Health IRCCS Burlo Garofolo, 34137 Trieste, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7432-4708","authenticated-orcid":false,"given":"Beatrice","family":"Spedicati","sequence":"additional","affiliation":[{"name":"Institute for Maternal and Child Health IRCCS Burlo Garofolo, 34137 Trieste, Italy"},{"name":"Department of Medicine, Surgery and Health Sciences, University of Trieste, 34129 Trieste, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6290-445X","authenticated-orcid":false,"given":"Anna","family":"Morgan","sequence":"additional","affiliation":[{"name":"Institute for Maternal and Child Health IRCCS Burlo Garofolo, 34137 Trieste, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Irene","family":"Bruno","sequence":"additional","affiliation":[{"name":"Institute for Maternal and Child Health IRCCS Burlo Garofolo, 34137 Trieste, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Massimo","family":"Zeviani","sequence":"additional","affiliation":[{"name":"Institute for Maternal and Child Health IRCCS Burlo Garofolo, 34137 Trieste, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4397-9143","authenticated-orcid":false,"given":"Cristina","family":"Dallabona","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, 43124 Parma, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4507-6589","authenticated-orcid":false,"given":"Giorgia","family":"Girotto","sequence":"additional","affiliation":[{"name":"Institute for Maternal and Child Health IRCCS Burlo Garofolo, 34137 Trieste, Italy"},{"name":"Department of Medicine, Surgery and Health Sciences, University of Trieste, 34129 Trieste, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5099-6526","authenticated-orcid":false,"given":"Andrea","family":"Magnolato","sequence":"additional","affiliation":[{"name":"Institute for Maternal and Child Health IRCCS Burlo Garofolo, 34137 Trieste, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1062","DOI":"10.1002\/1873-3468.13995","article-title":"Mitochondrial Disorders of the 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