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.
Gene. 2013 Dec 1;531(2):191-8. doi: 10.1016/j.gene.2013.09.018. Epub 2013 Sep 11.
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.
亚硫酸盐氧化酶 (SO) 缺乏症的生化特征是组织中硫酸盐、硫代硫酸盐和 S-磺基半胱氨酸的积累和高尿排泄。受影响的患者表现出严重的神经症状和皮质萎缩，其病理生理学仍未得到充分确立。因此，在本工作中，我们研究了亚硫酸盐和硫代硫酸盐对幼鼠大脑能量代谢重要参数的体外影响。我们验证了亚硫酸盐适度抑制了复合物 IV 的活性，而硫代硫酸盐没有改变呼吸链复合物的任何活性。还发现亚硫酸盐和硫代硫酸盐显著降低了总肌酸激酶 (CK) 及其线粒体和细胞质同工酶的活性，表明这些代谢物损害了脑细胞的能量缓冲和转移。相比之下，亚硫酸盐或硫代硫酸盐对突触 Na(+)，K(+)-ATPase 的活性没有影响。我们还观察到，亚硫酸盐和硫代硫酸盐对 CK 活性的抑制作用被褪黑素、还原型谷胱甘肽和两者的抗氧化剂组合以及一氧化氮合酶 N(ω)-硝基-l-精氨酸甲酯所预防，表明活性氧和氮物种参与了这些作用。亚硫酸盐和硫代硫酸盐还增加了 2'，7'-二氯荧光素的氧化和过氧化氢的产生，并降低了氧化还原传感器顺乌头酸酶的活性，加强了这些代谢物引起的氧化损伤作用。可以推测，亚硫酸盐和硫代硫酸盐引起的细胞能量和氧化还原平衡紊乱导致了 SO 缺乏症患者的神经症状和异常。
