Altered Metabolic Flexibility in Inherited Metabolic Diseases of Mitochondrial Fatty Acid Metabolism

• Published in: International journal of molecular sciences 2021-04, Vol.22 (7), p.3799
• Main Authors: Tucci, Sara, Alatibi, Khaled Ibrahim, Wehbe, Zeinab
• Format: Article
• Language: English
• Subjects: Acyl-CoA dehydrogenase; Adenosine triphosphate; Animals; Bacterial Proteins - metabolism; Biosynthesis; Coenzyme A Ligases - deficiency; Coenzyme A Ligases - metabolism; Congenital Bone Marrow Failure Syndromes - genetics; Congenital Bone Marrow Failure Syndromes - metabolism; Congenital Bone Marrow Failure Syndromes - pathology; Dehydrogenases; Disease; Energy; Energy balance; Enzymes; Fatty acids; Fatty Acids - genetics; Fatty Acids - metabolism; Flexibility; Glycolysis; Homeostasis; Humans; Lipid Metabolism, Inborn Errors - genetics; Lipid Metabolism, Inborn Errors - metabolism; Lipid Metabolism, Inborn Errors - pathology; Lipogenesis; Mammals; Metabolic Diseases - genetics; Metabolic Diseases - metabolism; Metabolic Diseases - pathology; Metabolic disorders; Metabolites; Mice; Mitochondria; Mitochondria - genetics; Mitochondria - metabolism; Mitochondria - pathology; Mitochondrial Diseases - genetics; Mitochondrial Diseases - metabolism; Mitochondrial Diseases - pathology; Muscles; Muscular Diseases - genetics; Muscular Diseases - metabolism; Muscular Diseases - pathology; Musculoskeletal system; Mutation; Oxidation; Oxidation rate; Proteins; Review; Skeletal muscle; Triglycerides
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms22073799

In general, metabolic flexibility refers to an organism's capacity to adapt to metabolic changes due to differing energy demands. The aim of this work is to summarize and discuss recent findings regarding variables that modulate energy regulation in two different pathways of mitochondrial fatty metabolism: β-oxidation and fatty acid biosynthesis. We focus specifically on two diseases: very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) and malonyl-CoA synthetase deficiency (acyl-CoA synthetase family member 3 (ACSF3)) deficiency, which are both characterized by alterations in metabolic flexibility. On the one hand, in a mouse model of VLCAD-deficient (VLCAD ) mice, the white skeletal muscle undergoes metabolic and morphologic transdifferentiation towards glycolytic muscle fiber types via the up-regulation of mitochondrial fatty acid biosynthesis (mtFAS). On the other hand, in ACSF3-deficient patients, fibroblasts show impaired mitochondrial respiration, reduced lipoylation, and reduced glycolytic flux, which are compensated for by an increased β-oxidation rate and the use of anaplerotic amino acids to address the energy needs. Here, we discuss a possible co-regulation by mtFAS and β-oxidation in the maintenance of energy homeostasis.