Language

English

Publication Date

5-30-2026

Journal

Nature Communications

DOI

10.1038/s41467-026-73455-9

PMID

42218136

PMCID

PMC13392013

PubMedCentral® Posted Date

5-30-2026

PubMedCentral® Full Text Version

Post-print

Abstract

Primary mitochondrial diseases (PMDs) affect approximately 1 in 4300 individuals and cause early-onset neuromuscular and multisystem dysfunction with reduced lifespan. They result from pathogenic variants in mitochondrial or nuclear DNA that impair oxidative phosphorylation. Cytochrome c oxidase (COX; complex IV) deficiency is a well-established cause of PMD, leading to a broad spectrum of phenotypes. COXFA4 (cytochrome c oxidase subunit FA4), formerly NDUFA4, is a nuclear-encoded COX subunit, but its role in disease remains poorly defined. We report the largest genetically confirmed cohort of COXFA4-related PMD to date, comprising 13 individuals from 12 families with biallelic pathogenic COXFA4 variants. All present with Leigh-like encephalopathy and complete loss of COXFA4 protein; however, patient-derived fibroblasts retain residual COX activity, with upregulation of COXFA4L2 (cytochrome c oxidase subunit FA4-like 2), a poorly characterised paralog. Here, we show that COXFA4 is a late-stage COX assembly subunit and identify a paralog-mediated compensatory mechanism with translational potential.

Keywords

Humans, Electron Transport Complex IV, Leigh Disease, Up-Regulation, Fibroblasts, Mitochondrial Diseases, Female, Male, Mitochondria, Mutation, Pedigree, Energy metabolism, Neuromuscular disease, Mechanisms of disease

Published Open-Access

yes

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