Tiranti Valeria, Viscomi Carlo, Hildebrandt Tatjana, Di Meo Ivano, Mineri Rossana, Tiveron Cecilia, Levitt Michael D, Prelle Alessandro, Fagiolari Gigliola, Rimoldi Marco, Zeviani Massimo
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.
Nat Med. 2009 Feb;15(2):200-5. doi: 10.1038/nm.1907. Epub 2009 Jan 11.
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.
乙基丙二酸脑病是一种常染色体隐性、必然致命的疾病，其特征为早发性脑病、微血管病、慢性腹泻、肌肉和脑中细胞色素c氧化酶（COX）缺陷、血液中C4和C5酰基肉碱浓度升高以及尿中乙基丙二酸排泄增加。ETHE1是一种编码β-内酰胺酶样铁配位金属蛋白的基因，在乙基丙二酸脑病中发生突变。在细菌中，ETHE1样序列与硫转移酶罗丹明编码基因TST的直系同源基因位于同一操纵子中或与之融合。在真核生物中，ETHE1和罗丹明都位于线粒体基质中。我们创建了一种Ethe1(-/-)小鼠，它表现出乙基丙二酸脑病的主要特征。我们发现，硫代硫酸盐在Ethe1(-/-)小鼠和患有乙基丙二酸脑病的人类尿液中大量排泄。Ethe1(-/-)小鼠组织中存在高浓度的硫代硫酸盐和硫化物。硫化物是COX和短链脂肪酸氧化的强力抑制剂，具有血管活性和血管毒性作用，这解释了乙基丙二酸脑病患者的微血管病。硫化物通过包括硫双加氧酶的线粒体途径解毒。Ethe1(-/-)小鼠中不存在硫双加氧酶活性，而在HeLa细胞和大肠杆菌中ETHE1过表达可使其显著增加。因此，ETHE1是一种参与硫化物分解代谢的线粒体硫双加氧酶，在乙基丙二酸脑病中硫化物会累积到有毒水平。
