Abstract
Mitochondrial fatty acid β-oxidation (FAO) is the primary pathway for fatty acid metabolism in humans, performing a key role in liver, heart and skeletal muscle energy homeostasis. FAO is particularly important during times of fasting when glucose supply is limited, providing energy for many organs and tissues, including the heart, liver and brain. Deficiencies in FAO can cause life-threatening metabolic disorders in early childhood that present with liver dysfunction, hypoglycemia, dilated hypertrophic cardiomyopathy and Reye-like Syndrome. Alternatively, FAO defects can also cause ‘milder’ adult-onset disease with exercise-induced myopathy and rhabdomyolysis. Short-chain enoyl-CoA hydratase (ECHS1) is a key FAO enzyme involved in the metabolism of fatty acyl-CoA esters. ECHS1 deficiency (ECHS1D) also causes human disease; however, the clinical manifestation is unlike most other FAO disorders. ECHS1D patients commonly present with Leigh syndrome, a lethal form of subacute necrotizing encephalomyelopathy traditionally associated with defects in oxidative phosphorylation (OXPHOS). In this article, we review the clinical, biochemical and genetic features of the ESHS1D patients described to date, and discuss the significance of the secondary OXPHOS defects associated with ECHS1D and their contribution to overall disease pathogenesis.
Highlights
Forty patients have been described with pathogenic mutations in ECHS1 since the identification of the first two patients with ECHS1 deficiency (ECHS1D) in 2014
Like other fatty acid β-oxidation (FAO) deficiencies, secondary oxidative phosphorylation (OXPHOS) defects in ECHS1D may be due to the accumulation of toxic fatty acid and/or valine metabolites, which can directly inhibit OXPHOS
The effects of these metabolites may be indirect by disrupting the interaction between the pyruvate dehydrogenase complex (PDC) and OXPHOS complex I
Summary
Mitochondria are the ‘powerhouses’ of the cell, producing 95% of all cellular energy in the form of adenosine triphosphate (ATP) [1]. Through a series of four enzymatic reactions, dehydrogenation, hydration, a second dehydrogenation and thiolysis, fatty acyl-CoA chains within the mitochondria are processed to yield one acetyl-CoA molecule, two electrons and a fatty acyl-CoA shortened by two carbons. This series of reactions is performed repeatedly until only two acetyl-CoA molecules remain (commonly termed the β-oxidation spiral) (Figure 1). Both dehydrogenation steps are cofactor-dependent, resulting in the reduction of NAD+ and FAD to NADH and FADH2 , which are subsequently oxidized by OXPHOS complexes I and II respectively [7]. For medium- and short-chain fatty acids, the last three steps of FAO are catalyzed by short-chain enoyl-CoA hydratase (ECHS1), hydroxyacyl-CoA dehydrogenase (HADH) and 3-ketoacyl-CoA thiolase (KAT) (Figure 1)
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