Loss of ETHE1, a mitochondrial dioxygenase, causes fatal sulfide toxicity in ethylmalonic encephalopathy

authored by: Valeria Tiranti, Carlo Viscomi, Tatjana Hildebrandt, Ivano Di Meo, Rossana Mineri, Cecilia Tiveron, Michael D Levitt, Alessandro Prelle, Gigliola Fagiolari, Marco Rimoldi, Massimo Zeviani
Abstract: Ethylmalonic encephalopathy is an autosomal recessive, invariably fatal disorder characterized by early-onset encephalopathy, microangiopathy, chronic diarrhea, defective cytochrome c oxidase (COX) in muscle and brain, high concentrations of C4 and C5 acylcarnitines in blood and high excretion of ethylmalonic acid in urine. ETHE1, a gene encoding a β-lactamase-like, iron-coordinating metalloprotein, is mutated in ethylmalonic encephalopathy. In bacteria, ETHE1-like sequences are in the same operon of, or fused with, orthologs of TST, the gene encoding rhodanese, a sulfurtransferase. In eukaryotes, both ETHE1 and rhodanese are located within the mitochondrial matrix. We created a Ethe1^-/- mouse that showed the cardinal features of ethylmalonic encephalopathy. We found that thiosulfate was excreted in massive amounts in urine of both Ethe1^-/- mice and humans with ethylmalonic encephalopathy. High thiosulfate and sulfide concentrations were present in Ethe1^-/- mouse tissues. Sulfide is a powerful inhibitor of COX and short-chain fatty acid oxidation, with vasoactive and vasotoxic effects that explain the microangiopathy in ethylmalonic encephalopathy patients. Sulfide is detoxified by a mitochondrial pathway that includes a sulfur dioxygenase. Sulfur dioxygenase activity was absent in Ethe1^-/- mice, whereas it was markedly increased by ETHE1 overexpression in HeLa cells and Escherichia coli. Therefore, ETHE1 is a mitochondrial sulfur dioxygenase involved in catabolism of sulfide that accumulates to toxic levels in ethylmalonic encephalopathy.
External Organisation(s): Istituto Nazionale Neurologico C Besta, Milan
University Hospital Düsseldorf
European Brain Research Institute Rita Levi-Montalcini (EBRI)
VA Medical Center
University of Milan - Bicocca
Type: Article
Journal: Nature medicine
Volume: 15
Pages: 200-205
No. of pages: 6
ISSN: 1078-8956
Publication date: 02.2009
Publication status: Published
Peer reviewed: Yes
ASJC Scopus subject areas: Biochemistry, Genetics and Molecular Biology(all)
Sustainable Development Goals: SDG 3 - Good Health and Well-being
Electronic version(s): https://doi.org/10.1038/nm.1907 (Access: Unknown)

BibTeX

@article{1ce15ab721494565b3a51b9f9523955b,
title = "Loss of ETHE1, a mitochondrial dioxygenase, causes fatal sulfide toxicity in ethylmalonic encephalopathy",
abstract = "Ethylmalonic encephalopathy is an autosomal recessive, invariably fatal disorder characterized by early-onset encephalopathy, microangiopathy, chronic diarrhea, defective cytochrome c oxidase (COX) in muscle and brain, high concentrations of C4 and C5 acylcarnitines in blood and high excretion of ethylmalonic acid in urine. ETHE1, a gene encoding a β-lactamase-like, iron-coordinating metalloprotein, is mutated in ethylmalonic encephalopathy. In bacteria, ETHE1-like sequences are in the same operon of, or fused with, orthologs of TST, the gene encoding rhodanese, a sulfurtransferase. In eukaryotes, both ETHE1 and rhodanese are located within the mitochondrial matrix. We created a Ethe1-/- mouse that showed the cardinal features of ethylmalonic encephalopathy. We found that thiosulfate was excreted in massive amounts in urine of both Ethe1-/- mice and humans with ethylmalonic encephalopathy. High thiosulfate and sulfide concentrations were present in Ethe1-/- mouse tissues. Sulfide is a powerful inhibitor of COX and short-chain fatty acid oxidation, with vasoactive and vasotoxic effects that explain the microangiopathy in ethylmalonic encephalopathy patients. Sulfide is detoxified by a mitochondrial pathway that includes a sulfur dioxygenase. Sulfur dioxygenase activity was absent in Ethe1-/- mice, whereas it was markedly increased by ETHE1 overexpression in HeLa cells and Escherichia coli. Therefore, ETHE1 is a mitochondrial sulfur dioxygenase involved in catabolism of sulfide that accumulates to toxic levels in ethylmalonic encephalopathy.",
author = "Valeria Tiranti and Carlo Viscomi and Tatjana Hildebrandt and {Di Meo}, Ivano and Rossana Mineri and Cecilia Tiveron and {D Levitt}, Michael and Alessandro Prelle and Gigliola Fagiolari and Marco Rimoldi and Massimo Zeviani",
note = "Funding Information: We thank A. Bradley (The Wellcome Trust Sanger Institute) for AB1 mouse embryonic stem cells. We are grateful to M. Bada for skillful technical assistance; to B. Garavaglia, E. Lamantea, F. Forlani and M.K. Grieshaber for valuable discussion; to the Chemical Analysis Laboratory, University of Georgia, for metal analysis; and to Primm for MALDI TOF mass spectometry analysis. This work was supported by the Pierfranco and Luisa Mariani Foundation Italy, Fondazione Telethon-Italy grant number GGP07019, the Italian Ministry of University and Research (FIRB 2003—project RBLA038RMA), MITOCIRCLE and EUMITOCOMBAT network grants from the European Union framework program 6 and by the Deutsche Forschungsgemeinschaft (GR 456/22-1).",
year = "2009",
month = feb,
doi = "10.1038/nm.1907",
language = "English",
volume = "15",
pages = "200--205",
journal = "Nature medicine",
issn = "1078-8956",
publisher = "Nature Publishing Group",
number = "2",
}