COXFA4L2 upregulation preserves residual cytochrome c oxidase activity in COXFA4-related Leigh-like encephalopathy
- 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
2026-05-30
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.