medrxiv2026-10-19score 95
Biallelic UQCC1 variants are a cause of mitochondrial complex III deficiency
Smith, Taylor and colleagues assign UQCC1, a complex III assembly factor not previously tied to human disease, as a recessive cause of early-onset mitochondrial disease with lactic acidosis. Nine people from eight families carry biallelic UQCC1 variants. Patient fibroblasts lose UQCC1 and its partner UQCC2, lose CIII2 on BN-PAGE and proteomics, delay insertion of new CIII subunits into native assemblies, and fail respiratory supercomplexes. Lentiviral UQCC1 restores protein and CIII2 activity. Complex III (ubiquinol:cytochrome c oxidoreductase) moves electrons from ubiquinol (QH2) to cytochrome c, then to Complex IV. Its catalytic metal sites are heme bL, heme bH, heme c1, and the Rieske [2Fe-2S] cluster. This abstract shows assembly and activity loss. It does not show which cofactor insertion step UQCC1 fails, and it does not report cluster spectroscopy.
