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Visualization of Mitochondrial Respiratory Function using Cytochrome C Oxidase / Succinate Dehydrogenase COX/SDH Double-labeling Histochemistry
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Visualization of Mitochondrial Respiratory Function using Cytochrome C Oxidase / Succinate Dehydrogenase COX/SDH Double-labeling Histochemistry

Published on: November 23, 2011

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Mutation in mitochondrial complex IV subunit COX5A causes pulmonary arterial hypertension, lactic acidemia, and

Fabian Baertling1,2, Fathiya Al-Murshedi3, Laura Sánchez-Caballero1

  • 1Department of Pediatrics, Radboud Centre for Mitochondrial Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands.

Human Mutation
|March 2, 2017
PubMed

Insights

Pathogenic variants in the COX5A gene cause early-onset pulmonary arterial hypertension and complex IV deficiency. Copper supplementation offers a potential therapeutic strategy for this mitochondrial disorder.

Area of Science:

  • Biochemistry
  • Genetics
  • Mitochondrial Biology

Background:

  • Mitochondrial respiratory chain complex IV (cytochrome c oxidase) is crucial for cellular respiration.
  • COX5A is a nuclear-encoded subunit essential for complex IV assembly and function.
  • Mutations in COX5A can lead to severe clinical manifestations due to impaired oxidative phosphorylation.

Purpose of the Study:

  • To investigate the clinical and molecular consequences of a homozygous pathogenic variant in the COX5A gene.
  • To elucidate the role of COX5A in complex IV biogenesis and identify potential therapeutic interventions.

Main Methods:

  • Clinical phenotyping of patients with COX5A variants.
  • Analysis of complex IV activity and subunit levels in patient-derived fibroblasts.
  • Lentiviral complementation and copper supplementation assays.

Main Results:

  • Identified homozygous pathogenic variants in COX5A in siblings with early-onset pulmonary arterial hypertension, lactic acidemia, and failure to thrive.
  • Demonstrated reduced complex IV activity and protein levels in patient fibroblasts, with accumulation of COX1 assembly intermediate.
  • Showed that lentiviral complementation rescues complex IV deficiency and copper supplementation partially restores function.

Conclusions:

  • Pathogenic COX5A variants disrupt complex IV biogenesis, leading to severe mitochondrial disease.
  • COX5A plays a critical role in the assembly of complex IV.
  • Copper supplementation represents a promising therapeutic avenue for COX5A-related mitochondrial disorders.

Keywords:
COX5AOXPHOScomplex IVcytochrome c oxidasepulmonary arterial hypertension

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