COXFA4L2 upregulation preserves residual cytochrome c oxidase activity in COXFA4-related Leigh-like encephalopathy

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.

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Journal
Nature Communications
Published
2026-05-30
DOI
https://doi.org/10.1038/s41467-026-73455-9
Primary Topic
Mitochondrial Function and Pathology
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article
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article

COXFA4L2 upregulation preserves residual cytochrome c oxidase activity in COXFA4-related Leigh-like encephalopathy

Joseph J Gleeson, Rıza Köksal Özgül, Sadia Riaz, Chiara Pizzamiglio et al.
Nature Communications
Mitochondrial Function and Pathology
article

COXFA4L2 upregulation preserves residual cytochrome c oxidase activity in COXFA4-related Leigh-like encephalopathy

Joseph J Gleeson, Rıza Köksal Özgül, Sadia Riaz, Chiara Pizzamiglio, Michael G. Hanna, Anna Lucia Francavilla, Jonathan Lévy, Giulia Barcia, William L. Macken, Cristina Ugalde, Renata Kabiljo, Pauline Gaignard, Erika Fernández‐Vizarra, Micol Falabella, Jan‐Willem Taanman, Maqbool Hussain, Efstathia Chronopoulou, Ciro Leonardo Pierri, Ali Dursun, William J. Craigen, Germaine Pierre, Jana Aref, Aboulfazl Rad, Maha S. Zaki, Lisa Emrick, Gehad Elmakkawy, Jamie K. Leighton, Khalil Ur Rehman, JiHye Kim, Helen Mundy, Reza Maroofian, Gabriela Oprea, Henry Houlden, Javeria Raza Alvi, Rebecca Halligan, Antoine Pouzet, Sandra Lopez Calcerrada, Robert D. S. Pitceathly, Jiaze Gao, Robert A. Taylor, Jill A. Rosenfeld, Tipu Sultan, Vincent Procaccio
article en

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.

Nature Communications
Hôpital Necker-Enfants Malades (FR), Centre National de la Recherche Scientifique (FR), Children’s Institute (US), Inserm (FR), Queen Mary University of London (GB), Baylor College of Medicine (US), Guy's and St Thomas' NHS Foundation Trust (GB), Université Paris Cité (FR), Universidad de Zaragoza (ES), Université Paris-Saclay (FR), University Hospitals Bristol NHS Foundation Trust (GB), Newcastle upon Tyne Hospitals NHS Foundation Trust (GB), University of California San Diego (US), Research Institute Hospital 12 de Octubre (ES), Assistance Publique – Hôpitaux de Paris (FR), Technologie Médicale (France) (FR), Centre for Biomedical Network Research on Rare Diseases (ES), Centro de Investigación Biomédica en Red (ES), UK Dementia Research Institute (GB), Hôpital Robert-Debré (FR), National Research Centre (EG), Wellcome Centre for Mitochondrial Research (GB), Centro de Investigaciones Biológicas Margarita Salas (ES), CS Diagnostics (DE), National Hospital for Neurology and Neurosurgery (GB), Baylor Genetics (US), Bicêtre Hospital (FR), Institut des Maladies Génétiques Imagine (FR), Sabzevar University of Medical Sciences (IR), University College London (GB), Université d'Angers (FR), Pakistan Institute of Medical Sciences (PK), University of Bari Aldo Moro (IT), Hacettepe University (TR), Alexandria University (EG), Newcastle University (GB)
Wellcome Trust, Muscular Dystrophy UK, LifeArc, Cancer Research UK, National Institute for Health and Care Research, Department of Health and Social Care, Rosetrees Trust, Medical Research Council
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