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<p>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 <i>c</i> oxidase (COX; complex IV) deficiency is a well-established cause of PMD, leading to a broad spectrum of phenotypes. COXFA4 (cytochrome <i>c</i> 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 <i>COXFA4</i> 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 <i>c</i> 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.</p>

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年5月30日

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

摘要

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.