{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T15:51:50Z","timestamp":1774626710629,"version":"3.50.1"},"reference-count":23,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T00:00:00Z","timestamp":1774569600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Brazilian Rare Genome Project"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Introduction: Ubiquinol\u2013cytochrome c reductase core protein II (UQCRC2) encodes a core subunit of the mitochondrial electron transport chain (ETC) complex III (CIII). Biallelic pathogenic variants in UQCRC2 have been associated with mitochondrial disease characterized by lactic acidosis, developmental delay, hepatopathy, and episodic metabolic decompensation. Methods: We reviewed the biochemical phenotypes of 14 individuals possessing UQCRC2 variants, including two novel cases. We performed biochemical studies of mitochondrial respiration and oxidative phosphorylation (OXPHOS) complex measurements in patient-derived fibroblasts. Results: We report reduced CIII activity in a majority of individuals possessing variants in UQCRC2, as well as biochemical findings consistent with impaired mitochondrial energy metabolism, though impairments in mitochondrial respiration were variable. The two previously unreported, unrelated patients possessing the likely pathogenic missense variant c.361T&gt;C, p.Tyr121His in UQCRC2 in trans with a 16p12.2 microdeletion encompassing UQCRC2 showed milder phenotypes, less severe metabolic decompensations, and no long-term neurological impairments. Both individuals display reduced CIII activity and mitochondrial respiratory dysfunction. Discussion: These data expand the current understanding of genotypes associated with UQCRC2-associated mitochondrial disease to include the novel 16p12.2 microdeletion. These data also highlight the consistent biochemical phenotype associated with UQCRC2-associated mitochondrial disease, and the need for consistent biochemical and respiratory assessment of individuals possessing UQCRC2 variants to further our understanding of this phenotype.<\/jats:p>","DOI":"10.3390\/cells15070596","type":"journal-article","created":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T14:33:33Z","timestamp":1774622013000},"page":"596","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Reversible Metabolic and Liver Disease in Complex III Deficiency: Novel Variants Expand the Reported UQCRC2-Associated Phenotype"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6810-9326","authenticated-orcid":false,"given":"Graeme","family":"Preston","sequence":"first","affiliation":[{"name":"Department of Clinical Genomics, Mayo Clinic, 200 1st St. SW, Rochester, MN 55905, USA"},{"name":"Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, 1425 Madison Ave, New York, NY 10029, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1486-9722","authenticated-orcid":false,"given":"Ibrahim","family":"Shammas","sequence":"additional","affiliation":[{"name":"Department of Clinical Genomics, Mayo Clinic, 200 1st St. SW, Rochester, MN 55905, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6030-1903","authenticated-orcid":false,"given":"Filippo","family":"Pinto e Vairo","sequence":"additional","affiliation":[{"name":"Department of Clinical Genomics, Mayo Clinic, 200 1st St. SW, Rochester, MN 55905, USA"},{"name":"Department of Medicine, Division of Gastroenterology and Hepatology, Mayo Clinic, 200 1st St. SW, Rochester, MN 55905, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna","family":"Ligezka","sequence":"additional","affiliation":[{"name":"Department of Clinical Genomics, Mayo Clinic, 200 1st St. SW, Rochester, MN 55905, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-1799-4589","authenticated-orcid":false,"given":"Carlos Alberto de Moura","family":"Aschoff","sequence":"additional","affiliation":[{"name":"Post Graduate Program in Genetics and Molecular Biology, Federal University of Rio Grande do Sul, Avenida Osvaldo Aranha, 338, Porto Alegre 90040-060, RS, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0804-2876","authenticated-orcid":false,"given":"Fabiano","family":"Poswar","sequence":"additional","affiliation":[{"name":"Post Graduate Program in Genetics and Molecular Biology, Federal University of Rio Grande do Sul, Avenida Osvaldo Aranha, 338, Porto Alegre 90040-060, RS, Brazil"},{"name":"Medical Genetics Service, Hospital de Clinicas de Porto Alegre, Rua Ramiro Barcelos 2350, Porto Alegre 90035-003, RS, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ida Vanessa D.","family":"Schwartz","sequence":"additional","affiliation":[{"name":"Post Graduate Program in Genetics and Molecular Biology, Federal University of Rio Grande do Sul, Avenida Osvaldo Aranha, 338, Porto Alegre 90040-060, RS, Brazil"},{"name":"Medical Genetics Service, Hospital de Clinicas de Porto Alegre, Rua Ramiro Barcelos 2350, Porto Alegre 90035-003, RS, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tamas","family":"Kozicz","sequence":"additional","affiliation":[{"name":"Department of Clinical Genomics, Mayo Clinic, 200 1st St. SW, Rochester, MN 55905, USA"},{"name":"Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, 1425 Madison Ave, New York, NY 10029, USA"},{"name":"Department of Anatomy, University of Pecs Medical School, Pecs Szigeti \u00fat, 12 7624 Pecs, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7441-700X","authenticated-orcid":false,"given":"Eva","family":"Morava","sequence":"additional","affiliation":[{"name":"Department of Clinical Genomics, Mayo Clinic, 200 1st St. SW, Rochester, MN 55905, USA"},{"name":"Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, 1425 Madison Ave, New York, NY 10029, USA"},{"name":"Department of Biophysics, University of Pecs Medical School, Pecs Szigeti \u00fat, 12 7624 Pecs, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1038\/s41580-021-00415-0","article-title":"The assembly, regulation and function of the mitochondrial respiratory chain","volume":"23","author":"Vercellino","year":"2022","journal-title":"Nat. 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