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.
Highlights
The term “metabolic flexibility” was first used in the context of helminths to describe the generation of chemical energy and key metabolites that provided them with the metabolic flexibility to respond and adapt to changes in their environment [1]
We focus on two diseases of mitochondrial fatty acid metabolism, i.e., very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) and malonyl-CoA synthetase deficiency (acyl-CoA synthetase family member 3 (ACSF3) deficiency)
The processes of β-oxidation, linked to adenosine triphosphate (ATP) production, and mitochondrial fatty acid biosynthesis are both localized in the mitochondria
Summary
The term “metabolic flexibility” was first used in the context of helminths to describe the generation of chemical energy and key metabolites that provided them with the metabolic flexibility to respond and adapt to changes in their environment [1]. In humans, this term refers to the selection of fuel by the organism, in different situations, toward fulfilling its energy needs by matching fuel availability [2]. Several inherited metabolic diseases negatively affect energy metabolism, and its dysregulation in fatty acid oxidation disorders have been described [10,11,12,13,14,15]. We discuss how monogenic diseases themselves as well as other variables, such as sex and diet, affect metabolic flexibility, and how both pathways interact to maintain energy homeostasis
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