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 beta-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.

• Authors: Valeria Tiranti, Carlo Viscomi, Tatjana Hildebrandt, Ivano Di Meo, Rossana Mineri, Cecilia Tiveron, Michael D Levitt, Alessandro Prelle, Gigliola Fagiolari, Marco Rimoldi, Massimo Zeviani
• Journal: Nature medicine (Nat Med) Vol. 15 Issue 2 Pg. 200-5 (Feb 2009) ISSN: 1546-170X [Electronic] United States
• PMID: 19136963 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA Primers
• ETHE1 protein, human
• Malonates
• Mitochondrial Proteins
• Nucleocytoplasmic Transport Proteins
• Sulfides
• ethylmalonic acid
• Dioxygenases
• ETHE1 protein, mouse

Topics

• Animals
• Base Sequence
• Brain Diseases (chemically induced, pathology)
• DNA Primers
• Dioxygenases (genetics, physiology)
• HeLa Cells
• Humans
• Malonates (toxicity)
• Mice
• Mice, Knockout
• Mitochondria (enzymology)
• Mitochondrial Proteins (genetics, physiology)
• Nucleocytoplasmic Transport Proteins (genetics, physiology)
• Polymerase Chain Reaction
• Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
• Sulfides (toxicity)