Deficiency of the mitochondrial persulfide dioxygenase ETHE1 causes proteome-wide alterations in ethylmalonic encephalopathy patient fibroblasts

Abstract

Deficiency of the mitochondrial persulfide dioxygenase ETHE1 causes proteome-wide alterations in ethylmalonic encephalopathy patient fibroblastsThe mitochondrial persulfide dioxygenase ETHE1 is essential for clearance of the gasotransmitter hydrogen sulfide, and ETHE1 deficiency causes a severe and complex inherited metabolic disorder known as ethylmalonic encephalopathy. Despite well-described clinical symptoms of the disease [1], detailed molecular characterization is still ambiguous. The objective was to obtain a better understanding of the molecular effects of deficiency of the sulfide regulating enzyme ETHE1, by applying proteomics. Materials and methods: Quantitative MS-based proteomics was performed on cultivated skin fibroblasts originating from patients and controls. Results: The cultured cells exhibited only a mild phenotype with few pronounced proteomic changes of central metabolic pathways; however, the data captured more than hundred regulated proteins indicating broad effects on cellular physiology. Functional pathway analyses exhibited overrepresentation of nucleic acid binding transcription factors, glycoproteins and translational regulators. Discussion and conclusions: These proteomics data show a complementary picture to previous metabolomics data [2], and describe how ETHE1 deficiency can trigger changes not only in mitochondria but also throughout the cell.