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Lookup NU author(s): Jamie Leighton, Professor Robert TaylorORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© The Author(s) 2026.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.
Author(s): Falabella M, Lopez Calcerrada S, Aref J, Gao J, Macken WL, Pizzamiglio C, Kabiljo R, Francavilla AL, Gaignard P, Pouzet A, Levy J, Barcia G, Leighton JK, Chronopoulou E, Pierre G, Koksal Ozgul R, Dursun A, Halligan R, Mundy H, Raza Alvi J, Sultan T, Craigen WJ, Emrick L, Rosenfeld JA, Elmakkawy G, Kim J, Gleeson JJ, Rad A, Oprea G, Hussain M, Rehman KU, Riaz S, Taylor RW, Procaccio V, Zaki MS, Fernandez-Vizarra E, Pierri CL, Hanna MG, Houlden H, Maroofian R, Ugalde C, Taanman J-W, Pitceathly RDS
Publication type: Article
Publication status: Published
Journal: Nature Communications
Year: 2026
Volume: 17
Online publication date: 30/05/2026
Acceptance date: 27/04/2026
Date deposited: 04/08/2026
ISSN (electronic): 2041-1723
Publisher: Nature Research
URL: https://doi.org/10.1038/s41467-026-73455-9
DOI: 10.1038/s41467-026-73455-9
Data Access Statement: The authors confirm that the data supporting the findings of this study are available within the article and/or its Supplementary Information. Source data for all immunoblots are provided with the paper. [More at https://www.nature.com/articles/s41467-026-73455-9#data-availability ]
PubMed id: 42218136
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