Dysfunctional Electron Transport Chain Assembly in COXPD8.

Area of Science:

• Mitochondrial biology
• Genetics
• Biochemistry

Background:

• Combined oxidative phosphorylation deficiency type 8 (COXPD8) is a severe autosomal recessive mitochondrial disorder.
• It results from mutations in the nuclear-encoded mitochondrial alanyl-tRNA synthetase gene (AARS2).
• Clinical features include infantile hypertrophic cardiomyopathy, pulmonary hypoplasia, muscle weakness, and neurological issues.

Purpose of the Study:

• To investigate the molecular mechanisms underlying COXPD8 in a patient with novel AARS2 mutations.
• To analyze the impact of these mutations on mitochondrial respiratory chain complex assembly and function.
• To characterize the bioenergetic consequences of AARS2 mutations.

Main Methods:

• Genetic analysis of AARS2 gene mutations (c.1738 C>G and c.2872 C>T).
• Analysis of cardiac tissue using the LungMAP program to assess electron transport chain (ETC) complex assembly and supercomplex formation.
• Protein expression analysis of ETC components and tricarboxylic acid cycle enzymes.

Main Results:

• The patient harbored two AARS2 mutations, one previously unreported.
• These mutations disrupted the assembly of functional monomeric complexes I and IV of the ETC.
• Reduced formation of respiratory supercomplexes and altered expression of some ETC proteins were observed, alongside normal expression of key TCA cycle enzymes.

Conclusions:

• The identified AARS2 mutations are associated with failed assembly of ETC complexes I and IV.
• Reduced respiratory supercomplex formation contributes to bioenergetic stress in COXPD8.
• These findings elucidate the molecular pathology of COXPD8 and highlight the role of AARS2 in mitochondrial function.