Bi-allelic UQCC1 variants impair mitochondrial complex III assembly causing early-onset mitochondrial disease
- 1Newcastle University
Abstract
Mitochondrial disease arises from variants in either the mitochondrial or nuclear genome that impair mitochondrial oxidative phosphorylation. Complex III (ubiquinol:cytochrome c oxidoreductase, CIII2) is a key enzyme of the mitochondrial respiratory chain, catalyzing electron transfer from reduced coenzyme Q10 (ubiquinol) to complex IV, via cytochrome c. CIII2 has one subunit encoded by mitochondrial DNA, the remainder being nuclear encoded. Individuals with CIII2 deficiency present with significant clinical heterogeneity, on account of pathogenic variants in genes encoding structural CIII2 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 CIII2 abundance whilst mass spectrometry (MS)-complexome profiling corroborated these findings, identifying impaired respiratory supercomplex formation and a delay in the incorporation of newly synthesized CIII2 subunits into native assemblies. Lentiviral transduction experiments in subject-derived fibroblasts restored the levels of both UQCC1 protein and CIII2 activity. Collectively, these findings provide convergent genetic, biochemical, proteomic and functional evidence that biallelic UQCC1 variants disrupt CIII2 assembly, establishing UQCC1 deficiency as a cause of mitochondrial CIII2 deficiency.
Related
- Novel biallelic PATL2 variants causing predominant germinal vesicle arrest and recurrent ART failure: expanded mutational spectrum and evidence-based reproductive counseling guidance
- Pathogenic Mitofusin 2 variants causing myopathy drive endosomal mtDNA release and inflammation
- SLC10A1 variants causing NTCP deficiency in infants: clinical and functional characterization of a novel splice-site variant
- Maternally inherited PRKAR1A pathogenic variant causing Carney complex with a concomitant LDLR variant resulting in hyperlipidemia: a case report
- Characterization of Ataxia-linked MFN2 Variants Reveals a Lipid Droplet/Mitochondrial Axis Driving Ferroptosis
BibTeX
@misc{taylor2026biallelic,
title = {{Bi-allelic UQCC1 variants impair mitochondrial complex III assembly causing early-onset mitochondrial disease}},
author = {R. W. Taylor and S. J. Smith and S. Ait-El-Mkadem Saadi and J. K. Leighton and L. S. Taylor and A. M. Frey and M. G. Nelson and P. Castaneda-Tamez and E. C. Genin and R. Caswell and A. Dannoura and H. E. Shamsheldin and K. Fragaki and C. Rouzier and L. He and C. V. Y. Hemingbrough and M. R. Fassad and A. Fouilhoux and T. Shuaib and E. Alharby and P. Rehsi and R. Rodenburg and T. Rinne and M. C. H. Janssen and M. O. Hashem and H. Hamid and K. Bakur and H. Alrabee and S. Mohamed and R. M. Alansari and M. Al-Owain and E. L. Blakely and M. Winter and N. A. M. Almontashiri and A. A. Morris and L. AlAbdi and F. S. Alkuraya and H. K. Robinson and R. McFarland and C. L. Alston},
howpublished = {medRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.19.26365523},
url = {https://www.medrxiv.org/content/10.64898/2026.10.19.26365523v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Bi-allelic UQCC1 variants impair mitochondrial complex III assembly causing early-onset mitochondrial disease
AU - R. W. Taylor
AU - S. J. Smith
AU - S. Ait-El-Mkadem Saadi
AU - J. K. Leighton
AU - L. S. Taylor
AU - A. M. Frey
AU - M. G. Nelson
AU - P. Castaneda-Tamez
AU - E. C. Genin
AU - R. Caswell
AU - A. Dannoura
AU - H. E. Shamsheldin
AU - K. Fragaki
AU - C. Rouzier
AU - L. He
AU - C. V. Y. Hemingbrough
AU - M. R. Fassad
AU - A. Fouilhoux
AU - T. Shuaib
AU - E. Alharby
AU - P. Rehsi
AU - R. Rodenburg
AU - T. Rinne
AU - M. C. H. Janssen
AU - M. O. Hashem
AU - H. Hamid
AU - K. Bakur
AU - H. Alrabee
AU - S. Mohamed
AU - R. M. Alansari
AU - M. Al-Owain
AU - E. L. Blakely
AU - M. Winter
AU - N. A. M. Almontashiri
AU - A. A. Morris
AU - L. AlAbdi
AU - F. S. Alkuraya
AU - H. K. Robinson
AU - R. McFarland
AU - C. L. Alston
PY - 2026
DA - 2026/10/19
PB - medRxiv
DO - 10.64898/2026.10.19.26365523
UR - https://www.medrxiv.org/content/10.64898/2026.10.19.26365523v1
AB - Mitochondrial disease arises from variants in either the mitochondrial or nuclear genome that impair mitochondrial oxidative phosphorylation. Complex III (ubiquinol:cytochrome c oxidoreductase, CIII2) is a key enzyme of the mitochondrial respiratory chain, catalyzing electron transfer from reduced coenzyme Q10 (ubiquinol) to complex IV, via cytochrome c. CIII2 has one subunit encoded by mitochondrial DNA, the remainder being nuclear encoded. Individuals with CIII2 deficiency present with significant clinical heterogeneity, on account of pathogenic variants in genes encoding structural CIII2 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 CIII2 abundance whilst mass spectrometry (MS)-complexome profiling corroborated these findings, identifying impaired respiratory supercomplex formation and a delay in the incorporation of newly synthesized CIII2 subunits into native assemblies. Lentiviral transduction experiments in subject-derived fibroblasts restored the levels of both UQCC1 protein and CIII2 activity. Collectively, these findings provide convergent genetic, biochemical, proteomic and functional evidence that biallelic UQCC1 variants disrupt CIII2 assembly, establishing UQCC1 deficiency as a cause of mitochondrial CIII2 deficiency.
ER -