Dominant negative ATP5F1A variants disrupt oxidative phosphorylation causing neurological disorders

Area of Science:

• Biochemistry
• Genetics
• Molecular Biology

Background:

• ATP5F1A encodes the alpha-subunit of mitochondrial complex V, crucial for ATP synthesis.
• Defects in complex V can lead to severe neurological and developmental disorders.
• Understanding ATP5F1A variants is key to diagnosing and treating mitochondrial diseases.

Purpose of the Study:

• To investigate the impact of novel heterozygous de novo ATP5F1A missense variants.
• To elucidate the molecular and cellular mechanisms underlying ATP5F1A-associated neurodevelopmental disorders.
• To expand the known genotypic and phenotypic spectrum of ATP5F1A-related conditions.

Main Methods:

• Genetic sequencing to identify ATP5F1A variants in probands.
• Functional studies in C. elegans to assess variant pathogenicity.
• Biochemical assays, proteomics, and mitochondrial physiology studies in patient-derived cells.

Main Results:

• Six probands presented with developmental delay, intellectual disability, and movement disorders due to de novo ATP5F1A variants.
• All tested variants exhibited a dominant-negative effect on gene function in C. elegans.
• Proband cells showed reduced complex V abundance and activity, with uncoupled oxidative phosphorylation.

Conclusions:

• Heterozygous de novo ATP5F1A variants cause a distinct neurodevelopmental disorder with mitochondrial dysfunction.
• ATP5F1A is the most common nuclear gene cause of complex V deficiency.
• Functional studies are essential for interpreting the significance of ATP5F1A variants.