Loss of mitochondrial fatty acid β‐oxidation protein short‐chain Enoyl‐CoA hydratase disrupts oxidative phosphorylation protein complex stability and function

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 Syn...

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Bibliographic Details
Published in:The FEBS journal 2023-01, Vol.290 (1), p.225-246
Main Authors: Burgin, Harrison, Sharpe, Alice J., Nie, Shuai, Ziemann, Mark, Crameri, Jordan J., Stojanovski, Diana, Pitt, James, Ohtake, Akira, Murayama, Kei, McKenzie, Matthew
Format: Article
Language:English
Subjects:
Biosynthesis
CRISPR
Defects
ECHS1 deficiency
Electron transport chain
Enoyl-CoA Hydratase - genetics
Enoyl-CoA Hydratase - metabolism
Enzymatic activity
Esters
fatty acid oxidation
Fatty acids
Fatty Acids - metabolism
Fibroblasts
Functional analysis
Humans
Mitochondria
mitochondrial disease
Mitochondrial Proteins - genetics
Mitochondrial Proteins - metabolism
Nucleotides
Original
Oxidation
Oxidative Phosphorylation
Oxidoreductase
OXPHOS
Oxygen consumption
Pathogenesis
Phosphorylation
Proteins
Proteomics
short‐chain enoyl‐CoA hydratase
Substrates
Transcriptomes
Tricarboxylic acid cycle
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Summary: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. Short‐Chain Enoyl‐CoA Hydratase (ECHS1) is involved in mitochondrial fatty acid β‐oxidation (left). Loss of ECHS1 causes global gene expression changes that affect the tricarboxylic acid cycle and the electron transport chain (right). This affects complex I and IV activities, resulting in reduced mitochondrial respiratory function. Furthermore, ECHS1 appears to play a role in the assembly of complex I, with loss of ECHS1 associated with reduced complex I levels.
ISSN:1742-464X
1742-4658
DOI:10.1111/febs.16595