Understanding the role of OXPHOS dysfunction in the pathogenesis of ECHS1 deficiency

Abstract

Mitochondria provide the main source of energy for eukaryotic cells, oxidizing fatty acids and sugars to generate ATP. Mitochondrial fatty acid β‐oxidation (FAO) and oxidative phosphorylation (OXPHOS) are two key pathways involved in this process. Disruption of FAO can cause human disease, with patients commonly presenting with liver failure, hypoketotic glycaemia and rhabdomyolysis. However, patients with deficiencies in the FAO enzyme short‐chain enoyl‐CoA hydratase 1 (ECHS1) are typically diagnosed with Leigh syndrome, a lethal form of subacute necrotizing encephalomyelopathy that is normally associated with OXPHOS dysfunction. Furthermore, some ECHS1‐deficient patients also exhibit secondary OXPHOS defects. This sequela of FAO disorders has long been thought to be caused by the accumulation of inhibitory fatty acid intermediates. However, new evidence suggests that the mechanisms involved are more complex, and that disruption of OXPHOS protein complex biogenesis and/or stability is also involved. In this review, we examine the clinical, biochemical and genetic features of all ECHS1‐deficient patients described to date. In particular, we consider the secondary OXPHOS defects associated with ECHS1 deficiency and discuss their possible contribution to disease pathogenesis.

Characterization of the Metabolic, Clinical and Neuropsychological Phenotype of Female Carriers of the Premutation in the X-Linked FMR1 Gene

“…In conclusion, through a combined multi-omics approach in PBMC and plasma of PM females in association with thorough clinical and bioenergetics assessments, we found impaired metabolic pathways which can result from the direct action of toxic intermediates derived from the PM genetic background (either accumulation of mRNA or proteotoxicity of RANderived protein products). In this regard, we are adding the novel observation that the accumulation of aberrant metabolites resulting from deficiencies in critical metabolic steps may add to the altered interaction between fatty acid oxidation and the electron transport chain contributing to the overall OXPHOS decline as it has been described for ECHS1 deficiency (Burgin and McKenzie, 2020; Figure 3). In turn, either mechanism elicits a suboptimal activation of UPR and ERAD responses, setting a challenging scenario to withstand other, more severe forms of stress.…”

“…Then, the significant lower expression of ABAD and ECHS1 in female carriers makes them as interesting candidates to investigate further in terms of its regulation in the context of beta-amyloid and proteostasis. Furthermore, since the OXPHOS decline in ECHS1 deficiency has been attributed to the accumulation of inhibitory fatty acid intermediates and to the disruption of ETC Complex biogenesis and/or stability (Burgin and McKenzie, 2020), it would not be unlikely that these mechanisms are contributing to the OXPHOS deficiencies observed in the PM.…”

Thioesterase induction by 2,3,7,8-tetrachlorodibenzo-p-dioxin results in a futile cycle that inhibits hepatic β-oxidation

“…The expression of Hadha was not affected by TCDD. In contrast, ECHS1, the short chain enoyl-CoA hydratase, prefers C4 enoyl-CoAs with diminishing activity towards C10 enoyl-CoAs 54 . Although Echs1 transcript levels was repressed 2.0-fold in the presence of AHR enrichment and pDREs, protein levels were induced (Fig.…”

Dioxin-elicited decrease in cobalamin redirects hepatic propionyl-CoA metabolism to the β–oxidation-like pathway resulting in acrylyl-CoA conjugate accumulation

“…The HADHA enoyl-CoA hydratase subunit of MTP prefers longer chain (C12-16) enoyl substrates with minimal activity towards short chain (C4) enoyl-CoAs (Eaton et al, 2000). In contrast, the ECHS1 subunit prefers shorter chain (C4) enoyl-CoAs with diminishing binding affinity as enoyl-CoAs approach C10 in length (Burgin and McKenzie, 2020). Moreover, acrylyl-CoA is reported to be efficiently hydrated to 3-HP-CoA by ECHS1 (Shimomura et al, 1994).…”