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• W4291169785 endingPage "246" @default.
• W4291169785 startingPage "225" @default.
• W4291169785 abstract "Short-chain enoyl-CoA hydratase 1 (ECHS1) is involved in the second step of mitochondrial fatty acid β-oxidation (FAO), catalysing the hydration of short-chain enoyl-CoA esters to short-chain 3-hyroxyl-CoA esters. Genetic deficiency in ECHS1 (ECHS1D) is associated with a specific subset of Leigh Syndrome, a disease typically caused by defects in oxidative phosphorylation (OXPHOS). Here, we examined the molecular pathogenesis of ECHS1D using a CRISPR/Cas9 edited human cell 'knockout' model and fibroblasts from ECHS1D patients. Transcriptome analysis of ECHS1 'knockout' cells showed reductions in key mitochondrial pathways, including the tricarboxylic acid cycle, receptor-mediated mitophagy and nucleotide biosynthesis. Subsequent proteomic analyses confirmed these reductions and revealed additional defects in mitochondrial oxidoreductase activity and fatty acid β-oxidation. Functional analysis of ECHS1 'knockout' cells showed reduced mitochondrial oxygen consumption rates when metabolising glucose or OXPHOS complex I-linked substrates, as well as decreased complex I and complex IV enzyme activities. ECHS1 'knockout' cells also exhibited decreased OXPHOS protein complex steady-state levels (complex I, complex III2 , complex IV, complex V and supercomplexes CIII2 /CIV and CI/CIII2 /CIV), which were associated with a defect in complex I assembly. Patient fibroblasts exhibit varied reduction of mature OXPHOS complex steady-state levels, with defects detected in CIII2 , CIV, CV and the CI/CIII2 /CIV supercomplex. Overall, these findings highlight the contribution of defective OXPHOS function, in particular complex I deficiency, to the molecular pathogenesis of ECHS1D." @default.
• W4291169785 created "2022-08-13" @default.
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• W4291169785 date "2022-08-24" @default.
• W4291169785 modified "2023-10-15" @default.
• W4291169785 title "Loss of mitochondrial fatty acid <scp>β‐oxidation</scp> protein short‐chain <scp>Enoyl‐CoA</scp> hydratase disrupts oxidative phosphorylation protein complex stability and function" @default.
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• W4291169785 doi "https://doi.org/10.1111/febs.16595" @default.
• W4291169785 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/35962613" @default.

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