Dominant negative ATP5F1A variants disrupt oxidative phosphorylation causing neurological disorders

Area of Science:

• Biochemistry
• Genetics
• Neuroscience

Background:

• ATP5F1A encodes the alpha-subunit of mitochondrial complex V, essential for ATP synthesis.
• Complex V deficiency can result from genetic variants, impacting cellular energy production.
• Understanding ATP5F1A variants is crucial for diagnosing and treating mitochondrial disorders.

Purpose of the Study:

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

Main Methods:

• Described 6 probands with de novo ATP5F1A variants.
• Conducted functional studies in C. elegans.
• Performed biochemical, proteomics, and mitochondrial physiology studies on proband-derived cells.

Main Results:

• Identified heterozygous de novo missense ATP5F1A variants associated with developmental delay, intellectual disability, and movement disorders.
• Demonstrated a dominant-negative mechanism for the identified variants.
• Observed reduced complex V abundance and activity, uncoupled oxidative phosphorylation, increased oxygen consumption, decreased mitochondrial membrane potential, and lower ATP levels.
• Reported ATP5F1A as the most frequent nuclear gene cause of complex V deficiency with 12 individuals now identified.

Conclusions:

• Novel ATP5F1A variants cause complex V deficiency through a distinct pathophysiological mechanism compared to previously reported variants.
• Functional studies are vital for understanding the significance of ATP5F1A variants.
• ATP5F1A is a significant genetic cause of complex V deficiency, impacting neurodevelopment and mitochondrial function.