Mitochondrial Dysfunction and Redox Homeostasis Impairment as Pathomechanisms of Brain Damage in Ethylmalonic Encephalop
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REVIEW PAPER
Mitochondrial Dysfunction and Redox Homeostasis Impairment as Pathomechanisms of Brain Damage in Ethylmalonic Encephalopathy: Insights from Animal and Human Studies Mateus Grings1 · Moacir Wajner1,2,3 · Guilhian Leipnitz1,2 Received: 13 May 2020 / Accepted: 29 September 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Ethylmalonic encephalopathy (EE) is a severe intoxication disorder caused by mutations in the ETHE1 gene that encodes a mitochondrial sulfur dioxygenase involved in the catabolism of hydrogen sulfide. It is biochemically characterized by tissue accumulation of hydrogen sulfide and its by-product thiosulfate, as well as of ethylmalonic acid due to hydrogen sulfideinduced inhibition of short-chain acyl-CoA dehydrogenase. Patients usually present with early onset severe brain damage associated to encephalopathy, chronic hemorrhagic diarrhea and vascular lesions with petechial purpura and orthostatic acrocyanosis whose pathophysiology is poorly known. Current treatment aims to reduce hydrogen sulfide accumulation, but does not significantly prevent encephalopathy and most fatalities. In this review, we will summarize the present knowledge obtained from human and animal studies showing that disruption of mitochondrial and redox homeostasis may represent relevant pathomechanisms of tissue damage in EE. Mounting evidence show that hydrogen sulfide and ethylmalonic acid markedly disturb critical mitochondrial functions and induce oxidative stress. Novel therapeutic strategies using promising candidate drugs for this devastating disease are also discussed. Keywords Ethylmalonic encephalopathy · Ethylmalonic acid · Hydrogen sulfide · Mitochondria · Redox homeostasis · Brain damage
Introduction Ethylmalonic encephalopathy protein 1 (ETHE1) is a sulfur dioxygenase located in the mitochondrial matrix that participates in the degradation of hydrogen sulfide ( H2S), a compound derived from two major sources: the metabolism of anaerobic bacteria from the gut microbiota and the * Guilhian Leipnitz [email protected] 1
Programa de Pós‑Graduação em Ciências Biológicas: Bioquímica, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600‑Anexo, Porto Alegre, RS CEP 90035‑003, Brazil
2
Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600‑Anexo, Porto Alegre, RS CEP 90035‑003, Brazil
3
Serviço de Genética Médica, Hospital de Clínicas de Porto Alegre, Rua Ramiro Barcelos, 2350, Porto Alegre, RS 90035‑007, Brazil
catabolism of sulfur-containing amino acids. During the breakdown of methionine and cysteine, hydrogen sulfide is produced in the transsulfuration pathway by the enzymes cystathionine β-synthase, γ-cystathionase and 3-mercaptopyruvate sulfur transferase, being subsequently metabolized in the mitochondria (Fig. 1). In this organelle, hydrogen sulfide is oxidized by the enzyme sulfide quinone oxidoreductase, and the resultant sulfane sulfur is conjugated
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