title: Disturbance of brain energy and redox homeostasis provoked by sulfite and thiosulfate: potential pathomechanisms involved in the neuropathology of sulfite oxidase deficiency.
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 N(ω)-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.
authors.affiliation: 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.
authors.forename: Mateus
authors.initials: M
authors.lastname: Grings
authors.forename: Alana Pimentel
authors.initials: AP
authors.lastname: Moura
authors.forename: Belisa
authors.initials: B
authors.lastname: Parmeggiani
authors.forename: Gustavo Flora
authors.initials: GF
authors.lastname: Marcowich
authors.forename: Alexandre Umpierrez
authors.initials: AU
authors.lastname: Amaral
authors.forename: Angela Terezinha
authors.initials: AT
authors.lastname: de Souza Wyse
authors.forename: Moacir
authors.initials: M
authors.lastname: Wajner
authors.forename: Guilhian
authors.initials: G
authors.lastname: Leipnitz
mesh_terms: D000592:Amino Acid Metabolism, Inborn Errors / Q000150:complications* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D001928:Brain Diseases, Metabolic / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D004579:Electron Transport / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D004734:Energy Metabolism / Q000187:drug effects* / Q000502:physiology; D006706:Homeostasis / Q000187:drug effects*; D008297:Male; D010084:Oxidation-Reduction / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D050876:Sulfite Oxidase / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D013447:Sulfites / Q000378:metabolism / Q000494:pharmacology*; D013885:Thiosulfates / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D013447:Sulfites; D013885:Thiosulfates; D050876:Sulfite Oxidase
keywords: 2,6-dichloroindophenol; 2′,7′-dichlorofluorescein diacetate; 2′,7′-dichlorofluorescin; Bioenergetic dysfunction; CK; DCF; DCF-DA; DCFH; DCIP; GSH; L-NAME; MEL; N(ω)-nitro-l-arginine methyl ester; Pi; ROS; Rat brain; Reactive species; SO; Sulfite; Sulfite oxidase deficiency; TRO; Thiosulfate; cCK; creatine kinase; cytosolic creatine kinase; dichlorofluorescein; inorganic phosphate; mCK; melatonin; mitochondrial creatine kinase; reactive oxygen species; reduced glutathione; sulfite oxidase; tCK; total creatine kinase; trolox