Bi-allelic UQCC1 variants impair mitochondrial complex III assembly causing early-onset mitochondrial disease
Year: 2026
Type: preprint
Study design: Case Report
Abstract: Mitochondrial disease arises from variants in either the mitochondrial or nuclear genome that impair mitochondrial oxidative phosphorylation. Complex III (ubiquinol:cytochrome c oxidoreductase, CIII 2 ) is a key enzyme of the mitochondrial respiratory chain, catalyzing electron transfer from reduced coenzyme Q10 (ubiquinol) to complex IV, via cytochrome c . CIII 2 has one subunit encoded by mitochondrial DNA, the remainder being nuclear encoded. Individuals with CIII 2 deficiency present with significant clinical heterogeneity, on account of pathogenic variants in genes encoding structural CIII 2 subunits or assembly factors. UQCC1 (GenBank: NM_018244.5 ) encodes the mitochondrial complex III assembly factor ‘Ubiquinol-cytochrome c reductase complex assembly factor 1’, which is currently not associated with human disease. Here we describe nine subjects from eight unrelated families harboring biallelic UQCC1 variants with heterogeneous, early-onset mitochondrial disease presentations and lactic acidosis. Subject-derived fibroblasts demonstrated a decrease in the steady-state levels of UQCC1 and its interacting partner UQCC2, with structural modelling supportive of variant pathogenicity. BN-PAGE and quantitative proteomics demonstrated decreased CIII 2 abundance whilst mass spectrometry (MS)-complexome profiling corroborated these findings, identifying impaired respiratory supercomplex formation and a delay in the incorporation of newly synthesized CIII 2 subunits into native assemblies. Lentiviral transduction experiments in subject-derived fibroblasts restored the levels of both UQCC1 protein and CIII 2 activity. Collectively, these findings provide convergent genetic, biochemical, proteomic and functional evidence that biallelic UQCC1 variants disrupt CIII 2 assembly, establishing UQCC1 deficiency as a cause of mitochondrial CIII 2 deficiency.
Source: medRxiv
Authors: Sarah J. Smith, Samira Ait-El-Mkadem Saadi, Jamie K. Leighton, Lucie S. Taylor, Andrew M. Frey, Michael G. Nelson, Paulina Castañeda-Tamez, Emmanuelle C. Genin, Richard Caswell, Abeer Dannoura, Hanan E. Shamsheldin, Konstantina Fragaki, Cécile Rouzier, Langping He, Charlotte V. Y. Hemingbrough, Mahmoud R. Fassad, Alain Fouilhoux, Taghreed Shuaib, Essa Alharby, Preeya Rehsi, Richard J. Rodenburg, Tuula Rinne, Mirian C. H. Janssen, Mais O. Hashem, Halima Hamid, Khadijah Bakur, Hadeel Alrabee, Sarar Mohamed, Rahaf M. Alansari, Mohammed Al-Owain, Emma L. Blakely, Monika Winter, Naif A. M. Almontashiri, Andrew A. Morris, Lama AlAbdi, Fowzan S. Alkuraya, Hannah K. Robinson, Robert McFarland, Charlotte L. Alston, Véronique Paquis-Flucklinger, Ilka Wittig, Robert W. Taylor
Institutions: Newcastle upon Tyne Hospitals NHS Foundation Trust, Centre National de la Recherche Scientifique, Inserm, Centre Hospitalier Universitaire de Nice, Institut de Recherche sur le Cancer et le Vieillissement de Nice, Newcastle University, Goethe University Frankfurt, Royal Devon & Exeter NHS Foundation Trust, Royal Devon University Healthcare NHS Foundation Trust, King Faisal Specialist Hospital & Research Centre, Hospices Civils de Lyon, King Abdulaziz University, Taibah University, Great Ormond Street Hospital, Great Ormond Street Hospital for Children NHS Foundation Trust, Radboud University Medical Center, Riyadh Armed Forces Hospital, Alfaisal University, National University, Northumbria University, King Khaled Eye Specialist Hospital, University of Manchester, Manchester University NHS Foundation Trust
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Awards: G1028242125, G1902814985, Pleiotropic disorders of mitochondrial translation, G3794036287, Wartung und Reparatur von mitochondrialen Proteinkomplexen, G4978291889, Can muscle biopsy be avoided for paediatric patients with suspected mitochondrial disease?, G5549861300, G7327507430, SFB 1531: Schadenskontrolle durch das Stromavaskuläre Kompartiment, G8644597529
OpenAlex ID: W7222932365