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.
Acknowledgements
We gratefully acknowledge the participants of the National Genomic Research Library (NGRL), whose contributions made this research possible. Secure access to the NGRL under project ID [RR445] was provided by Genomics England, which delivers the NGRL in partnership with NHS England, and is wholly owned by the UK Department of Health and Social Care. The NGRL contains participants’ health data collected by the NHS as part of their care, along with samples and data from their participation in research, for which fully informed consent has been obtained. This includes genomic and clinical data provided through the NHS Genomic Medicine Service, as well as data obtained through research studies, including the 100,000 Genomes Project and the Generation Study, both of which are delivered in partnership with the NHS, and from other research cohorts involving external collaborators. This research was also supported by access to data and findings from the 100,000 Genomes Project and by matchmaking through the RD-Connect Genome-Phenome Analysis Platform. The 100,000 Genomes Project is managed by Genomics England Limited (a wholly owned company of the Department of Health and Social Care) and funded by the National Institute for Health and Care Research and NHS England. Research infrastructure was also supported by the Wellcome Trust, Cancer Research UK, and the Medical Research Council. We are deeply grateful to the affected individuals and their families for their invaluable contribution to this study. We also thank Cathy E. Woodward, Yogen Patel, and Robyn Labrum (Neurogenetics Unit, Rare and Inherited Disease Laboratory, North Thames Genomic Laboratory Hub, London, UK); Amanda Lam and Simon J. R. Heales (Neurometabolic Unit, The National Hospital for Neurology and Neurosurgery, London, UK); Iwona Skorupinska, Mariola Skorupinka, Louise Germain, and Esra Erdil (NHS Highly Specialised Service for Rare Mitochondrial Disorders, Queen Square Centre for Neuromuscular Diseases, The National Hospital for Neurology and Neurosurgery, London, UK); Carl Fratter, Conrad Smith, and Kate Sergeant (Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, UK); Charlotte L. Alston (NHS Highly Specialised Service for Rare Mitochondrial Disorders of Adults and Children, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK); Stephanie Efthymiou, David Murphy, Ehsan Barkhordari, Shahryar Alavi, Rahema Mohammad, Reagan Lee, Valentina Turchetti, and Annarita Scardamaglia (University College London Queen Square Neurogenetics Laboratory, London, UK) for their expert support and collaboration.
Funding
R.D.S.P. and M.F. are supported by a UKRI Medical Research Council Transition Support award (MR/X02363X/1). R.D.S.P., M.F., and M.G.H. receive support from a UKRI Medical Research Council award (MC_PC_21046) to establish a National Mouse Genetics Network Mitochondria Cluster (MitoCluster). R.D.S.P., R.W.T., H.H., and M.G.H. are supported by a UKRI Medical Research Council strategic award (MR/S005021/1) to establish an International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD). R.D.S.P., R.W.T., and M.G.H. are supported by the LifeArc Centre to Treat Mitochondrial Diseases (G125217). LifeArc is a charity registered in England and Wales under no. 1015243 and in Scotland under no. SC037861. The opinions and interpretations presented are those of the authors and not LifeArc’s. R.D.S.P., H.H., and M.G.H. are supported by UKRI Medical Research Council (UK) award UKRI2547 – Finding the Missing Worldwide Causes of Inherited Neuromuscular Diseases. R.D.S.P., M.F., W.L.M., C.P., and R.W.T. are funded by the Lily Foundation. C.P. and R.D.S.P. are funded by Muscular Dystrophy UK (MDUK). R.D.S.P. is funded by a seedcorn award from the Rosetrees Trust and Stoneygate Foundation. A.L.F. and C.L.P. are supported by EU funding within the MUR PNRR National Center for Gene Therapy and Drugs based on RNA Technology (Project no. CN_00000041). R.W.T. receives additional funding from the Wellcome Centre for Mitochondrial Research (203105/Z/16/Z), the Pathological Society, the UK NIHR Biomedical Research Centre for Ageing and Age-related disease award to the Newcastle upon Tyne Foundation Hospitals NHS Trust, and the UK NHS Highly Specialised Service for Rare Mitochondrial Disorders of Adults and Children. C.U. is supported by Instituto de Salud Carlos III (PI20/00057) and Ministerio de Ciencia, Innovacion y Universidades, Spain (PID2023-147288NB-I00) and by the Caixa Research Health program (HR24-00604). J.-W.T. is supported by Fund 42 of the Royal Free Charity. The University College London Hospitals/University College London Queen Square Institute of Neurology sequencing facility receives a proportion of funding from the Department of Health’s National Institute for Health Research Biomedical Research Centres funding scheme. The clinical and diagnostic ‘Rare Mitochondrial Disorders’ Service in London is funded by the UK NHS Highly Specialised Commissioners.
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The Department of Molecular and Human Genetics at Baylor College of Medicine receives revenue from clinical genetic testing completed at Baylor Genetics Laboratories. Aboulfazl Rad and Gabriela Oprea are employed by the Company Arcensus GmbH. The remaining authors declare no competing interests.
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Falabella, M., Lopez Calcerrada, S., Aref, J. et al. COXFA4L2 upregulation preserves residual cytochrome c oxidase activity in COXFA4-related Leigh-like encephalopathy. Nat Commun (2026). https://doi.org/10.1038/s41467-026-73455-9
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DOI: https://doi.org/10.1038/s41467-026-73455-9
