Disturbance of brain energy and redox homeostasis provoked by sulfite and thiosulfate: Potential pathomechanisms involved in the neuropathology of sulfite oxidase deficiency
Disturbance of brain energy and redox homeostasis provoked by sulfite and thiosulfate: Potential pathomechanisms involved in the neuropathology of sulfite oxidase deficiency
复制标题
DOI：
10.1016/j.gene.2013.09.018
复制
发表时间：
2013-12-01
期刊：
影响因子：
3.5
通讯作者：
Leipnitz, Guilhian
中科院分区：
文献类型：
--
作者：
Grings, Mateus;Moura, Alana Pimentel;Leipnitz, Guilhian
亚硫酸盐氧化酶（SO）缺乏症的生化特征是亚硫酸盐、硫代硫酸盐和S-磺基半胱氨酸的组织蓄积和高尿排泄。受影响的患者表现出严重的神经系统症状和皮质萎缩，其病理生理学仍不明确。因此，在本工作中，我们研究了亚硫酸盐和硫代硫酸盐对年轻大鼠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复合物IV的活性，而硫代硫酸盐没有改变任何呼吸链复合物的活性。还发现亚硫酸盐和硫代硫酸盐显著降低总肌酸激酶（CK）及其线粒体和胞质异构体的活性，表明这些代谢物损害脑细胞能量缓冲和转移。相反，突触Na+，K +-ATP酶的活性不受亚硫酸盐或硫代硫酸盐的影响。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种抗氧化剂的组合以及一氧化氮合酶N-ω-硝基-L-精氨酸甲酯阻止，这表明活性氧和氮物质参与了这些作用。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，加强了氧化损伤在这些代谢产物引起的效应中的作用。可以推测，由亚硫酸盐和硫代硫酸盐引起的细胞能量和氧化还原稳态的紊乱有助于在受SO缺乏影响的患者中发现的神经症状和异常。(C)2013爱思唯尔有限公司版权所有。
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-omega-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. (C) 2013 Elsevier B.V. All rights reserved.