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

Valeria Tiranti, Carlo Viscomi, Tatjana Hildebrandt, Ivano Di Meo, Rossana Mineri, Cecilia Tiveron, Michael D Levitt, Alessandro Prelle, Gigliola Fagiolari, Marco Rimoldi, Massimo Zeviani

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)200-205
Number of pages6
JournalNature Medicine
Volume15
Issue number2
DOIs
Publication statusPublished - Feb 2009

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Dioxygenases
Sulfides
Toxicity
Thiosulfate Sulfurtransferase
Thiosulfates
Gene encoding
Metalloproteins
Volatile Fatty Acids
Poisons
Corrosion inhibitors
Electron Transport Complex IV
Chronic Brain Damage
Urine
Escherichia coli
Muscle
Brain
Bacteria
Oxidoreductases
Blood
Iron

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Tiranti, V., Viscomi, C., Hildebrandt, T., Di Meo, I., Mineri, R., Tiveron, C., ... Zeviani, M. (2009). Loss of ETHE1, a mitochondrial dioxygenase, causes fatal sulfide toxicity in ethylmalonic encephalopathy. Nature Medicine, 15(2), 200-205. https://doi.org/10.1038/nm.1907

Loss of ETHE1, a mitochondrial dioxygenase, causes fatal sulfide toxicity in ethylmalonic encephalopathy. / Tiranti, Valeria; Viscomi, Carlo; Hildebrandt, Tatjana; Di Meo, Ivano; Mineri, Rossana; Tiveron, Cecilia; D Levitt, Michael; Prelle, Alessandro; Fagiolari, Gigliola; Rimoldi, Marco; Zeviani, Massimo.

In: Nature Medicine, Vol. 15, No. 2, 02.2009, p. 200-205.

Research output: Contribution to journalArticle

Tiranti, V, Viscomi, C, Hildebrandt, T, Di Meo, I, Mineri, R, Tiveron, C, D Levitt, M, Prelle, A, Fagiolari, G, Rimoldi, M & Zeviani, M 2009, 'Loss of ETHE1, a mitochondrial dioxygenase, causes fatal sulfide toxicity in ethylmalonic encephalopathy', Nature Medicine, vol. 15, no. 2, pp. 200-205. https://doi.org/10.1038/nm.1907
Tiranti, Valeria ; Viscomi, Carlo ; Hildebrandt, Tatjana ; Di Meo, Ivano ; Mineri, Rossana ; Tiveron, Cecilia ; D Levitt, Michael ; Prelle, Alessandro ; Fagiolari, Gigliola ; Rimoldi, Marco ; Zeviani, Massimo. / Loss of ETHE1, a mitochondrial dioxygenase, causes fatal sulfide toxicity in ethylmalonic encephalopathy. In: Nature Medicine. 2009 ; Vol. 15, No. 2. pp. 200-205.
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