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.

Verdict. UQCC1 is now a human complex III assembly-factor gene. Biallelic variants remove CIII2 and supercomplexes; putting UQCC1 back restores activity.

Metal sites and redox

Complex III (ubiquinol:cytochrome c oxidoreductase, CIII2) oxidizes ubiquinol (QH2 / Q) and reduces cytochrome c. The catalytic metals, from established enzyme structure, are heme bL, heme bH, heme c1, and the Rieske [2Fe-2S] cluster (the [2Fe-2S]2+/+ couple in the Q-cycle). This paper does not report EPR, nuclearity, or a 2Fe versus 2Fe oxidation-level lesion. It reports that CIII2 does not accumulate, new subunits join native assemblies late, supercomplexes suffer, and CIII2 activity returns with UQCC1. UQCC1 is an assembly factor, historically tied to cytochrome b, not a cluster scaffold like ISCU. Say the machine that is missing contains those metal sites. Do not say UQCC1 is an Fe-S protein unless a later figure shows it.

What the authors report

Nine patients, eight families, biallelic UQCC1, early-onset mitochondrial disease, lactic acidosis. Fibroblasts: UQCC1 down, UQCC2 down, CIII2 down on BN-PAGE and proteomics, supercomplexes down, delayed CIII subunit incorporation on complexome, activity rescued by lentiviral UQCC1. Modeling supports that the variants are not polymorphisms.

What was measured

Genetics, UQCC1/UQCC2 protein, BN-PAGE, quantitative proteomics, MS-complexome, CIII2 activity, complementation.

Caveats

Preprint. No cofactor chemistry. Clinical spread not itemized in the abstract. Fibroblasts only for biochemistry.

What to do with it

Put UQCC1 on CIII-deficiency gene lists. The biochemical signature is CIII2 plus supercomplex loss with UQCC2 codepletion and a clean complementation. The chemical follow-up is whether cytochrome b heme insertion or Rieske addition is the stalled step.

Bibliographic record

Field	Value
Title	Bi-allelic UQCC1 variants impair mitochondrial complex III assembly causing early-onset mitochondrial disease
DOI	10.64898/2026.10.19.26365523
Server	medrxiv
Posted	2026-10-19
Topics	Complex III, OXPHOS assembly, mitochondrial disease, UQCC1, supercomplexes, Fe-S
Mitos score	89/100
Confidence	medium
HTML	https://www.medrxiv.org/content/10.64898/2026.10.19.26365523
PDF	https://www.medrxiv.org/content/10.64898/2026.10.19.26365523.full.pdf

Abstract-based editorial synthesis by Mitos. Not peer review.

Source preprint

Bi-allelic UQCC1 variants impair mitochondrial complex III assembly causing early-onset mitochondrial disease

10.64898/2026.10.19.26365523

Smith SJ, Saadi SA, Leighton JK, Taylor LS, Frey AM, Nelson MG, Castañeda-Tamez P, Genin EC, Caswell R, Dannoura A, Shamsheldin HE, Fragaki K, Rouzier C, He L, Hemingbrough CVY, Fassad MR, Fouilhoux A, Shuaib T, Alharby E, Rehsi P, Rodenburg RJ, Rinne T, Janssen MCH, Hashem MO, Hamid H, Bakur K, Alrabee H, Mohamed S, Alansari RM, Al-Owain M, Blakely EL, Winter M, Almontashiri NAM, Morris AA, AlAbdi L, Alkuraya FS, Robinson HK, McFarland R, Alston CL, Paquis-Flucklinger V, Wittig I, Taylor RW.

Signal profile (abstract-level)