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Untargeted Metabolomics Analysis Reveals a Link between ETHE1-Mediated Disruptive Redox State and Altered Metabolic Regulation
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<sup>+</sup> 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