Abstract
Very-long-chain acyl-coenzyme A dehydrogenase (VLCAD) is a coenzyme encoded by ACADVL that converts very-long-chain fatty acids into energy. This process is disrupted by c.65C > A; p.Ser22∗ mutation. To clarify mechanisms by which this mutation leads to VLCAD deficiency, we evaluated differences in molecular and cellular functions between mesenchymal stem cells with normal and mutant VLCAD. Saudi Arabia have a high incidence of this form of mutation. Stem cells with mutant VLCAD were isolated from skin of two patients. Metabolic activity and proliferation were evaluated. The Same evaluation was repeated on normal stem cells introduced with same mutation by CRISPR. Mitochondrial depiction was done by electron microscope and proteomic analysis was done on patients’ cells. Metabolic activity and proliferation were significantly lower in patients’ cells. Introducing the same mutation into normal stem cells resulted in the same defects. We detected mitochondrial abnormalities by electron microscopy in addition to poor wound healing and migration processes in mutant cells. Furthermore, in a proteomic analysis, we identified several upregulated or downregulated proteins related to hypoglycemia, liver disorder, and cardiac and muscle involvement. We concluded experimental assays of mutant ACADVL (c.65C > A; p.Ser22∗) contribute to severe neonatal disorders with hypoglycemia, liver disorder, and cardiac and muscle involvement.
Highlights
Fatty acid oxidation disorders are a collection of recessive disorders triggered by an insufficiency in enzymes involved in β-oxidation or the movement of long-chain fatty acids into the mitochondria
Cardiolipin binding is regulated by reversible lysine acylation; this mechanism is predicted to apply to other metabolic proteins that localize to the inner mitochondrial membrane (Zhang et al, 2015) and could explain hypertrophic cardiomyopathy in mice (Chen et al, 2016)
In mice with very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiency, there is little to no protein hyperacetylation in the liver, suggesting that VLCAD is necessary for protein acetylation in the species (Pougovkina et al, 2014)
Summary
Fatty acid oxidation disorders are a collection of recessive disorders triggered by an insufficiency in enzymes involved in β-oxidation or the movement of long-chain fatty acids into the mitochondria. Body energy is produced by mitochondria by a complex mechanism involving the fatty acid beta oxidation pathway, which delivers an important supply of energy; longchain fatty acids require carnitine transport ability to enter the mitochondria in order to produce ketone bodies, which provide a form of energy for the brain, heart, muscle, kidney, and other tissues (Sun and Merritt, 2015; Leslie et al, 2018). ACADVL encodes very-long-chain acyl-CoA dehydrogenase (VLCAD) and mutations in this gene can result in VLCAD deficiency (OMIM #201475). ACADVL interacts with esters of long-chain and very-longchain fatty acids (McAndrew et al, 2008). In mice with VLCAD deficiency, there is little to no protein hyperacetylation in the liver, suggesting that VLCAD is necessary for protein acetylation in the species (Pougovkina et al, 2014)
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