Novel ACADVL variants resulting in mitochondrial defects in long-chain acyl-CoA dehydrogenase deficiency

Area of Science:

• Biochemistry
• Molecular Biology
• Genetics

Background:

• The pathogenesis of very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiency is poorly understood and highly variable.
• Newly identified genetic variants require characterization to elucidate their functional impact.

Purpose of the Study:

• To investigate the molecular and cellular consequences of six novel missense variants associated with mild VLCAD deficiency.
• To understand the biochemical effects and structural implications of these previously unreported VLCAD variants.

Main Methods:

• Functional assessment of fatty acid oxidation (FAO) in patient-derived cells.
• Analysis of mitochondrial function, including respiratory chain activity and ATP production.
• Evaluation of reactive oxygen species (ROS) levels, apoptosis, and protein stability.
• Molecular dynamics (MD) simulations to predict structural changes in mutant VLCAD.

Main Results:

• All six novel variants caused significant deficiencies in FAO and mitochondrial dysfunction.
• Cells with mutant VLCAD exhibited reduced ATP production, increased mitochondrial ROS, and higher apoptosis under stress.
• MD simulations indicated altered homodimer stability and conformational changes in mutant VLCAD structures.

Conclusions:

• These novel VLCAD variants impair crucial cellular functions, contributing to disease heterogeneity.
• The findings offer insights into the molecular basis of VLCAD deficiency, aiding in diagnosis and therapeutic development.
• Understanding these variants is key to improving patient management and comprehending disease variability.