A Late-Onset and Mild Phenotype of Mitochondrial Complex I Deficiency Due to a Novel Reported Variant Within the ACAD9 Gene

Acyl-CoA dehydrogenase 9 deficiency is considered as a rare neuromuscular syndrome with an autosomal recessive transmission. The ACAD9 protein presents two essential functions, i.e., the limiting step enzyme of the fatty acid β-oxidation pathway and one of the complex's compounds involved in the respiratory chain complex I assembly. Thus, loss-of-function mutations are known to convey mitochondrial cytopathologies. A patient with a mild and late-onset phenotype, suffering from exercise intolerance and hypertrophic cardiomyopathy, was diagnosed as a compound heterozygote of the <i>ACAD9</i> gene. The first c.1240C> T p.Arg414Cys variant has been previously reported and is known to be responsible for <i>ACAD9</i> deficiency. However, the second c.1636G> A p.Val546Met variant has never been described. The goal was to investigate the eventual pathogenicity of this new genetic variant. For this purpose, molecular cloning was generated to express the <i>ACAD9</i> gene with the V546M variant in a cell line (ACAD9mut) and compared to cells expressing the wild-type <i>ACAD9</i>. Then, the mitochondrial respiration, ATP production, the mitochondrial network, and the oxidative phosphorylation's composition were investigated to reveal the effects of the V546M variant. While avoiding to affect the amount of the respiratory chain's complexes, the new <i>ACAD9</i> variant was entirely responsible for reducing over 50% of the mitochondrial complex I activity.