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

The Febs Journal · 10 authors, 10 centres

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The central result was that loss of ECHS1 led to reduced steady-state levels of multiple oxidative phosphorylation (OXPHOS) protein complexes and supercomplexes.

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This preclinical study investigated the molecular pathogenesis of ECHS1 deficiency, a cause of Leigh Syndrome, using CRISPR/Cas9 to create an ECHS1 knockout in 143B osteosarcoma cells. Co-immunoprecipitation suggested the loss of ECHS1 disrupts interactions with complex I subunits NDUFB11 and NDUFV3, potentially impairing complex I assembly. These findings provide evidence that loss of ECHS1 causes secondary defects in OXPHOS complex stability and assembly, contributing to the combined FAO and OXPHOS defects seen in patient cells.

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other

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neurology

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ORIGINAL PAPER

PMC10087869

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

The Febs Journal

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ABSTRACT

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 III 2 , complex IV, complex V and supercomplexes CIII 2 /CIV and CI/CIII 2 /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 CIII 2 , CIV, CV and the CI/CIII 2 /CIV supercomplex. Overall, these findings highlight the contribution of defective OXPHOS function, in particular complex I deficiency, to the molecular pathogenesis of ECHS1D. Keywords: ECHS1 deficiency, fatty acid oxidation, mitochondria, mitochondrial disease, OXPHOS, short‐chain enoyl‐CoA hydratase

CITATION EXPORT

Harrison Burgin, Alice J Sharpe, Shuai Nie et al.. Loss of mitochondrial fatty acid β‐oxidation protein short‐chain Enoyl‐CoA hydratase disrupts oxidative phosphorylation protein complex stability and function. The Febs Journal. (2022). https://doi.org/10.1111/febs.16595

AUTHORS

10 · 10 CENTRES

Harrison Burgin, Alice J Sharpe, Shuai Nie, Mark Ziemann, Jordan J Crameri, Diana Stojanovski, James Pitt, Akira Ohtake, Kei Murayama, Matthew McKenzie

1 School of Life and Environmental Sciences, Faculty of Science, Engineering and Built Environment, Deakin University, Geelong, Australia
2 Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Melbourne, Australia
3 Melbourne Mass Spectrometry and Proteomics Facility, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Australia
4 Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Australia
5 Department of Paediatrics, Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, The University of Melbourne, Australia
6 Department of Pediatrics & Clinical Genomics, Faculty of Medicine, Saitama Medical University, Japan
7 Centre for Intractable Diseases, Saitama Medical University Hospital, Japan
8 Department of Metabolism, Chiba Children's Hospital, Japan
9 Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Melbourne, Australia
10 Department of Molecular and Translational Science, Monash University, Melbourne, Australia