COXFA4L2 upregulation preserves residual cytochrome c oxidase activity in COXFA4-related Leigh-like encephalopathy
Abstract
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.
Article Details
Authors (43)
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
Mitochondrial Research Group, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom
Vincent Procaccio
Maha S. Zaki
Erika Fernández-Vizarra
Ciro Leonardo Pierri
Michael G. Hanna
Henry Houlden
Reza Maroofian
Cristina Ugalde
Jan-Willem Taanman
Robert D. S. Pitceathly