PXD032761

PXD032761 is an original dataset announced via ProteomeXchange.

Title	Loss of Mitochondrial Fatty Acid β-Oxidation Protein Short Chain Enoyl-CoA Hydratase Disrupts Oxidative Phosphorylation Protein Complex Stability and Function
Description	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 TCA 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). 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.
HostingRepository	PRIDE
AnnounceDate	2023-11-14
AnnouncementXML	Submission_2023-11-14_08:47:13.275.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD032761
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Shuai Nie
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090; scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Exploris 480

Revision	Datetime	Status	ChangeLog Entry
0	2022-03-23 08:06:45	ID requested
1	2023-05-10 13:51:34	announced
⏵ 2	2023-11-14 08:47:21	announced	2023-11-14: Updated project metadata.

10.6019/PXD032761;

Burgin H, Sharpe AJ, Nie S, Ziemann M, Crameri JJ, Stojanovski D, Pitt J, Ohtake A, Murayama K, McKenzie M, -oxidation protein short-chain Enoyl-CoA hydratase disrupts oxidative phosphorylation protein complex stability and function. FEBS J, 290(1):225-246(2023) [pubmed]

submitter keyword: mitochondria, OXPHOS, mitochondrial disease, ECHS1 deficiency, short chain enoyl-CoA hydratase, fatty acid oxidation

Matthew McKenzie
contact affiliation	1.School of Life and Environmental Sciences, Faculty of Science, Engineering and Built Environment, Deakin University, Geelong 3216, Australia 2.Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, 3168 Melbourne, Australia 3.Department of Molecular and Translational Science, Monash University, 3168 Melbourne, Australia
contact email	m.mckenzie@deakin.edu.au
lab head
Shuai Nie
contact affiliation	The University of Melbourne
contact email	shuai.nie@unimelb.edu.au
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD032761
     1. Label: PRIDE project
     2. Name: Loss of Mitochondrial Fatty Acid β-Oxidation Protein Short Chain Enoyl-CoA Hydratase Disrupts Oxidative Phosphorylation Protein Complex Stability and Function