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.
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Change history
20 January 2009
In the version of this article initially published online, ‘SDO’ should have been ‘SDH’ in Figure 4a,b. The error has been corrected for the print, PDF and HTML versions of this article.
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Acknowledgements
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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V.T. and M.Z. designed the experimental plan and wrote the manuscript; C.V. and C.T. took care of the creation of the Ethe1-knockout mouse; C.V. characterized the mouse phenotype; I.DM. carried out the measurements of the mitochondrial respiratory chain biochemistry; R.M. performed the experiments on expression and purification of the recombinant ETHE1 protein in E. coli; T.H. performed the sulfur-related enzymology; M.D.L. measured the sulfur compounds in body fluids and tissues; G.F. and A.P. carried out the morphological investigation; and M.R. took care of the metabolite analysis in urine and blood.
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Tiranti, V., Viscomi, C., Hildebrandt, T. et al. Loss of ETHE1, a mitochondrial dioxygenase, causes fatal sulfide toxicity in ethylmalonic encephalopathy. Nat Med 15, 200–205 (2009). https://doi.org/10.1038/nm.1907
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DOI: https://doi.org/10.1038/nm.1907
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