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In addition to mtDNA mutations, an increasing number of nucleus-encoded genes encoding mitochondrial proteins has been identified in association with mitochondrial encephalomyopathies. In several instances, investigation on unusual mitochondrial syndromes has revealed the existence of peculiar mechanisms of disease, and of new metabolic pathways and functions related to the formation and activity of the respiratory chain. For instance, ethylmalonic encephalopathy, EE, is an autosomal recessive, invariably fatal disorder characterized by early-onset brain failure, microangiopathy, chronic diarrhoea, defective cytochrome oxidase (COX) in muscle and brain, and high ethylmalonic acid (EMA). We found that ETHE1, a gene encoding a -lactamase-like, iron-coordinating metalloprotein, is mutated in EE. We observed that bacterial ETHE1-like sequences are in the same operon of, or fused with, RDS, a gene encoding rhodanese, a sulfurtransferase. Both ETHE1 and rhodanese are mitochondrial matrix proteins in eukaryotes. We created an Ethe1-less mouse that manifested the EE cardinal features and showed high thiosulfate and sulfide levels. Sulfide is a powerful inhibitor of COX and terminal -oxidation, with vasoactive effects that explain EE microangiopathy. Recent data obtained in worms, and confirmed in mice, showed that sulfide is detoxified in metazoans by a mitochondrial pathway that includes a sulfur dioxygenase (SDO). SDO activity was absent in Ethe1-/- mice, whereas ETHE1 overexpression in HeLa cells and E. coli markedly increased SDO activity. We conclude that ETHE1 is a mitochondrial SDO involved in the catabolism of sulfide, which accumulates to toxic levels in EE.