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

Abstract

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.

In vivo metabolic imaging identifies lipid vulnerability in a preclinical model of Her2+/Neu breast cancer residual disease and recurrence

“…Our transcriptional analysis indicated Etomoxir treatment additionally causes increases in Acsf3 expression, the gene responsible for producing malonyl-CoA from malonate within the mitochondria, in regressing and dormant tumors. Because malonate is a known succinate dehydrogenase and Complex II inhibitor, this increase in Acsf3 expression may further confirm our imaging results indicating the continued use of mitochondrial respiration as fuel even following Etomoxir treatment 63 , 64 . Finally, this transcriptional signature of increased fatty acid synthesis-related genes extends beyond time points directly treated with Etomoxir (i.e., dormant tumors), which may explain the chronic phenotypic changes of the extended survival following an acute treatment regime.…”

Short-Term Effect of a Low-Protein High-Carbohydrate Diet on Mature Female and Male, and Neomale Rainbow Trout

“…Coupled with the upregulation of the DNL, we also observed, in males and neomales, the attenuation of the β-oxidation. This is in accordance with what is commonly observed, as the DNL and β-oxidation are known to be regulated by several factors, including the nutritional status [ 26 , 27 ]. As for the glucose metabolism, we did not demonstrate differences between the NC and the HC diets regarding the lipid metabolism.…”

Investigation of the Association between the Energy Metabolism of the Insect Vector Laodelphax striatellus and Rice Stripe Virus (RSV)

“…For example, cancer cells can deregulate oxidative metabolism and utilize glycolysis to meet energy requirements, which is commonly known as the Warburg effect [ 29 , 30 ]. Fibroblasts of patients with malonyl-CoA synthase deficiencies show increased glycolytic flux, increased lipoylation and impaired mitochondrial respiration, which results in increased β-oxidation and the use of anaplerotic amino acids to supply energy needs [ 31 ]. In tumor cells with impaired oxidative phosphorylation, upregulation of the pentose phosphate pathway compensates for reduced energy yield [ 32 ].…”