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

Micol Falabella1, Sandra Lopez Calcerrada2, Jana Aref3

  • 1Department of Neuromuscular Diseases, University College London Queen Square Institute of Neurology, London, UK. m.falabella@ucl.ac.uk.

Nature Communications
|May 30, 2026
PubMed

Insights

Primary mitochondrial diseases (PMDs) are linked to COXFA4 gene variants. A compensatory mechanism involving COXFA4L2 may offer therapeutic potential for Leigh-like encephalopathy.

Area of Science:

  • Genetics
  • Biochemistry
  • Neurology

Background:

  • Primary mitochondrial diseases (PMDs) are genetic disorders affecting ~1 in 4300 individuals, causing early-onset neuromuscular and multisystem dysfunction.
  • Oxidative phosphorylation defects, particularly cytochrome c oxidase (COX; complex IV) deficiency, are common causes of PMDs with diverse clinical presentations.
  • The role of COXFA4 (cytochrome c oxidase subunit FA4), a nuclear-encoded COX subunit, in disease pathogenesis is not well understood.

Purpose of the Study:

  • To investigate the clinical and genetic spectrum of PMD caused by pathogenic variants in the COXFA4 gene.
  • To elucidate the molecular mechanisms underlying COXFA4 deficiency and identify potential compensatory pathways.
  • To explore the functional relationship between COXFA4 and its paralog, COXFA4L2.

Main Methods:

  • Genetic analysis of 13 individuals from 12 families with suspected PMD.
  • Assessment of COXFA4 protein levels and COX activity in patient-derived fibroblasts.
  • Analysis of COXFA4L2 expression and its role in COX assembly and activity.

Main Results:

  • Identified 13 individuals with biallelic pathogenic COXFA4 variants, presenting with Leigh-like encephalopathy and complete loss of COXFA4 protein.
  • Patient-derived fibroblasts showed residual COX activity despite absent COXFA4.
  • Upregulation of the poorly characterized paralog COXFA4L2 was observed, suggesting a compensatory mechanism.

Conclusions:

  • COXFA4 is a crucial late-stage assembly subunit of cytochrome c oxidase.
  • A paralog-mediated compensatory mechanism involving COXFA4L2 can partially restore COX activity in COXFA4-deficient cells.
  • This compensatory pathway holds translational potential for therapeutic strategies in COXFA4-related PMD.

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