Details
| Original language | English |
|---|---|
| Pages (from-to) | 200-205 |
| Number of pages | 6 |
| Journal | Nature medicine |
| Volume | 15 |
| Issue number | 2 |
| Publication status | Published - Feb 2009 |
| Externally published | Yes |
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 subject areas
- Biochemistry, Genetics and Molecular Biology(all)
- General Biochemistry,Genetics and Molecular Biology
Sustainable Development Goals
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In: Nature medicine, Vol. 15, No. 2, 02.2009, p. 200-205.
Research output: Contribution to journal › Article › Research › peer review
}
TY - JOUR
T1 - Loss of ETHE1, a mitochondrial dioxygenase, causes fatal sulfide toxicity in ethylmalonic encephalopathy
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).
PY - 2009/2
Y1 - 2009/2
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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=59649121556&partnerID=8YFLogxK
U2 - 10.1038/nm.1907
DO - 10.1038/nm.1907
M3 - Article
C2 - 19136963
AN - SCOPUS:59649121556
VL - 15
SP - 200
EP - 205
JO - Nature medicine
JF - Nature medicine
SN - 1078-8956
IS - 2
ER -