title: Untargeted Metabolomics Analysis Reveals a Link between ETHE1-Mediated Disruptive Redox State and Altered Metabolic Regulation.
abstract: Defects in the gene encoding the persulfide dioxygenase ETHE1 are known to cause the severe inherited metabolic disorder ethylmalonic encephalopathy (EE). In spite of known clinical characteristics, the molecular mechanisms underlying the ETHE1 deficiency are still obscure. Herein, to further analyze the molecular phenotype of the disease, we applied an untargeted metabolomics approach on cultivated fibroblasts of EE patients for pinpointing alterations in metabolite levels. Metabolites, as direct signatures of biochemical functions, can decipher biochemical pathways involved in the cellular phenotype of patient cells. Using liquid chromatography-mass spectrometry-based untargeted metabolomics, we identified 18 metabolites that have altered levels in fibroblasts from EE patients. Our data demonstrate disrupted redox state in EE patient cells, which is reflected by significantly decreased level of reduced glutathione. Furthermore, the down-regulation of several intermediate metabolites such as the redox cofactors NAD(+) and NADH as well as Krebs cycle intermediates revealed clear alteration in metabolic regulation. Pantothenic acid and several amino acids exhibited decreased levels, whereas the β-citrylglutamate with a putative role in brain development had an increased level in the EE patient cells. These observations indicate the severe impact of ETHE1 deficiency on cellular physiology and redox state, meanwhile suggesting targets for experimental studies on novel treatment options for the devastating metabolic disorder.
authors.affiliation: Research Unit for Molecular Medicine, Department of Clinical Medicine, Aarhus University and Aarhus University Hospital , Palle Juul-Jensens Boulevard 99, 8200 Aarhus N, Denmark.
authors.forename: Navid
authors.initials: N
authors.lastname: Sahebekhtiari
authors.affiliation: Section for Forensic Chemistry, Department of Forensic Medicine, Aarhus University , Palle Juul-Jensens Boulevard 99, 8200 Aarhus N, Denmark.
authors.forename: Camilla Bak
authors.initials: CB
authors.lastname: Nielsen
authors.affiliation: Section for Forensic Chemistry, Department of Forensic Medicine, Aarhus University , Palle Juul-Jensens Boulevard 99, 8200 Aarhus N, Denmark.
authors.forename: Mogens
authors.initials: M
authors.lastname: Johannsen
authors.affiliation: Research Unit for Molecular Medicine, Department of Clinical Medicine, Aarhus University and Aarhus University Hospital , Palle Juul-Jensens Boulevard 99, 8200 Aarhus N, Denmark.
authors.forename: Johan
authors.initials: J
authors.lastname: Palmfeldt
mesh_terms: D020739:Brain Diseases, Metabolic, Inborn / Q000209:etiology / Q000378:metabolism*; D002478:Cells, Cultured; D002853:Chromatography, Liquid; D015536:Down-Regulation; D005347:Fibroblasts / Q000166:cytology; D005786:Gene Expression Regulation; D006801:Humans; D008660:Metabolism / Q000235:genetics*; D055432:Metabolomics / Q000379:methods*; D024101:Mitochondrial Proteins / Q000172:deficiency*; D029543:Nucleocytoplasmic Transport Proteins / Q000172:deficiency*; D010084:Oxidation-Reduction; D011693:Purpura / Q000209:etiology / Q000378:metabolism*
chemical_list: C483228:ETHE1 protein, human; D024101:Mitochondrial Proteins; D029543:Nucleocytoplasmic Transport Proteins
keywords: ETHE1; amino acids; ethylmalonic encephalopathy; glutathione; metabolomics; pantothenic acid