Disturbance of brain energy and redox homeostasis provoked by sulfite and thiosulfate: Potential pathomechanisms involved in the neuropathology of sulfite oxidase deficiency |
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Authors: | Mateus Grings Alana Pimentel Moura Belisa Parmeggiani Gustavo Flora Marcowich Alexandre Umpierrez Amaral Angela Terezinha de Souza Wyse Moacir Wajner Guilhian Leipnitz |
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Institution: | 1. Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul (UFRGS), Rua Ramiro Barcelos, 2600-Anexo, CEP 90035-003 Porto Alegre, RS, Brazil;2. Serviço de Genética Médica, Hospital de Clínicas de Porto Alegre, Rua Ramiro Barcelos, 2350, CEP 90035-903 Porto Alegre, RS, Brazil |
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Abstract: | Sulfite oxidase (SO) deficiency is biochemically characterized by tissue accumulation and high urinary excretion of sulfite, thiosulfate and S-sulfocysteine. Affected patients present severe neurological symptoms and cortical atrophy, whose pathophysiology is still poorly established. Therefore, in the present work we investigated the in vitro effects of sulfite and thiosulfate on important parameters of energy metabolism in the brain of young rats. We verified that sulfite moderately inhibited the activity of complex IV, whereas thiosulfate did not alter any of the activities of the respiratory chain complexes. It was also found that sulfite and thiosulfate markedly reduced the activity of total creatine kinase (CK) and its mitochondrial and cytosolic isoforms, suggesting that these metabolites impair brain cellular energy buffering and transfer. In contrast, the activity of synaptic Na+,K+-ATPase was not altered by sulfite or thiosulfate. We also observed that the inhibitory effect of sulfite and thiosulfate on CK activity was prevented by melatonin, reduced glutathione and the combination of both antioxidants, as well as by the nitric oxide synthase Nω-nitro-l-arginine methyl ester, indicating the involvement of reactive oxygen and nitrogen species in these effects. Sulfite and thiosulfate also increased 2′,7′-dichlorofluorescin oxidation and hydrogen peroxide production and decreased the activity of the redox sensor aconitase enzyme, reinforcing a role for oxidative damage in the effects elicited by these metabolites. It may be presumed that the disturbance of cellular energy and redox homeostasis provoked by sulfite and thiosulfate contributes to the neurological symptoms and abnormalities found in patients affected by SO deficiency. |
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Keywords: | cCK cytosolic creatine kinase CK creatine kinase DCF dichlorofluorescein DCF-DA 2&prime 7&prime -dichlorofluorescein diacetate DCFH 2&prime 7&prime -dichlorofluorescin DCIP 2 6-dichloroindophenol GSH reduced glutathione L-NAME Nω-nitro-l-arginine methyl ester mCK mitochondrial creatine kinase MEL melatonin Pi inorganic phosphate ROS reactive oxygen species SO sulfite oxidase tCK total creatine kinase TRO trolox |
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