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

Publikation: Beitrag in Fachzeitschrift › Artikel › Forschung › Peer-Review

Autorschaft

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

Externe Organisationen

  • Istituto Nazionale Neurologico C Besta, Milan
  • Universitätsklinikum Düsseldorf
  • European Brain Research Institute Rita Levi-Montalcini (EBRI)
  • VA Medical Center
  • Università degli Studi di Milano-Bicocca (UNIMIB)
Forschungs-netzwerk anzeigen

Details

OriginalspracheEnglisch
Seiten (von - bis)200-205
Seitenumfang6
FachzeitschriftNature medicine
Jahrgang15
Ausgabenummer2
PublikationsstatusVeröffentlicht - Feb. 2009
Extern publiziertJa

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.

ASJC Scopus Sachgebiete

Ziele für nachhaltige Entwicklung

Zitieren

Loss of ETHE1, a mitochondrial dioxygenase, causes fatal sulfide toxicity in ethylmalonic encephalopathy. / Tiranti, Valeria; Viscomi, Carlo; Hildebrandt, Tatjana et al.
in: Nature medicine, Jahrgang 15, Nr. 2, 02.2009, S. 200-205.

Publikation: Beitrag in Fachzeitschrift › Artikel › Forschung › Peer-Review

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, Jg. 15, Nr. 2, S. 200-205. https://doi.org/10.1038/nm.1907
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, 15(2), 200-205. https://doi.org/10.1038/nm.1907
Tiranti V, Viscomi C, Hildebrandt T, Di Meo I, Mineri R, Tiveron C et al. Loss of ETHE1, a mitochondrial dioxygenase, causes fatal sulfide toxicity in ethylmalonic encephalopathy. Nature medicine. 2009 Feb;15(2):200-205. doi: 10.1038/nm.1907
Tiranti, Valeria ; Viscomi, Carlo ; Hildebrandt, Tatjana et al. / Loss of ETHE1, a mitochondrial dioxygenase, causes fatal sulfide toxicity in ethylmalonic encephalopathy. in: Nature medicine. 2009 ; Jahrgang 15, Nr. 2. S. 200-205.
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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).",
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AU - Tiranti, Valeria

AU - Viscomi, Carlo

AU - Hildebrandt, Tatjana

AU - Di Meo, Ivano

AU - Mineri, Rossana

AU - Tiveron, Cecilia

AU - D Levitt, Michael

AU - Prelle, Alessandro

AU - Fagiolari, Gigliola

AU - Rimoldi, Marco

AU - Zeviani, Massimo

N1 - 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).

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N2 - 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.

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