Antioxidant dysfunction: potential risk for neurotoxicity in ethylmalonic aciduria

Area of Science:

• Biochemistry
• Molecular Biology
• Genetics

Background:

• Mitochondrial dysfunction and oxidative stress are implicated in neuromuscular disabilities.
• Ethylmalonic aciduria (EMA) with ACADS c.625G>A homozygosity presents with neuromuscular symptoms.
• The specific factors initiating cell dysfunction in these patients remain unclear.

Purpose of the Study:

• To investigate the molecular basis of neuromuscular symptoms in patients with EMA and ACADS c.625G>A homozygosity.
• To identify factors contributing to cell dysfunction in these patients.
• To evaluate the role of mitochondrial dysfunction and oxidative stress.

Main Methods:

• Fibroblast cultures from 10 patients with EMA and ACADS c.625G>A homozygosity were analyzed.
• Functional analyses included ACADS gene/protein expression and SCAD enzyme activity.
• Mitochondrial proteome screening using nano-LC-MS/MS and oxidative stress sensitivity assays were performed.

Main Results:

• Loss of short-chain acyl-coenzyme A dehydrogenase (SCAD) function was observed, linked to decreased ACADS gene expression and/or protein degradation.
• Mitochondrial proteome analysis revealed reduced expression of superoxide dismutase 2 (SOD2).
• Patient fibroblasts exhibited significantly higher sensitivity to menadione-induced oxidative stress.

Conclusions:

• Reduced mitochondrial antioxidant capacity is a potential risk factor in ACADS c.625G>A-associated ethylmalonic aciduria.
• Mitochondrial dysfunction contributes to the neurotoxicity observed in these patients.
• Targeting mitochondrial dysfunction and oxidative stress may be beneficial for patient treatment.