Loss of ETHE1, a mitochondrial dioxygenase, causes fatal sulfide toxicity in ethylmalonic encephalopathy.
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.
Tiranti
Valeria
V
Pierfranco and Luisa Mariani Center for Research on Children's Mitochondrial Disorders, Institute of Neurology Carlo Besta-Istituto di Ricovero e Cura a Carattere Scientifico Foundation, Milan, Italy. tiranti@istituto-besta.it
Viscomi
Carlo
C
Hildebrandt
Tatjana
T
Di Meo
Ivano
I
Mineri
Rossana
R
Tiveron
Cecilia
C
Levitt
Michael D
MD
Prelle
Alessandro
A
Fagiolari
Gigliola
G
Rimoldi
Marco
M
Zeviani
Massimo
M
D000818:Animals; D001483:Base Sequence; D001927:Brain Diseases / Q000139:chemically induced / Q000473:pathology*; D017931:DNA Primers; D049308:Dioxygenases / Q000235:genetics / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D008314:Malonates / Q000633:toxicity*; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000201:enzymology*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000502:physiology*; D029543:Nucleocytoplasmic Transport Proteins / Q000235:genetics / Q000502:physiology*; D016133:Polymerase Chain Reaction; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013440:Sulfides / Q000633:toxicity*
D017931:DNA Primers; C483228:ETHE1 protein, human; D008314:Malonates; D024101:Mitochondrial Proteins; D029543:Nucleocytoplasmic Transport Proteins; D013440:Sulfides; C038080:ethylmalonic acid; D049308:Dioxygenases; C538757:ETHE1 protein, mouse