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 language | English |
|---|---|
| Pages (from-to) | 200-205 |
| Number of pages | 6 |
| Journal | Nature Medicine |
| Volume | 15 |
| Issue number | 2 |
| DOIs | |
| Publication status | Published - Feb 2009 |
Fingerprint
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)
- Medicine(all)
Cite this
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 journal › Article
}
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
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
UR - http://www.scopus.com/inward/citedby.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 -