Sulfite disrupts brain mitochondrial energy homeostasis and induces mitochondrial permeability transition pore opening via thiol group modification
Sulfite disrupts brain mitochondrial energy homeostasis and induces mitochondrial permeability transition pore opening via thiol group modification
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DOI：
10.1016/j.bbadis.2014.04.022
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发表时间：
2014-09-01
影响因子：
6.2
通讯作者：
Leipnitz, Guilhian
中科院分区：
文献类型：
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作者：
Grings, Mateus;Moura, Alana P.;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-磺基半胱氨酸在受影响患者的组织和生物体液中的积累。其主要临床症状为严重的神经功能障碍和脑部异常，其病理生理机制尚不清楚。本文研究了亚硫酸盐和硫代硫酸盐对离体大鼠脑线粒体内稳态的影响。证实了亚硫酸盐本身，而不是硫代硫酸盐，降低状态3，CCCP刺激状态和呼吸控制率在线粒体呼吸与谷氨酸和苹果酸。与此一致，我们发现亚硫酸盐抑制谷氨酸和苹果酸（MDH）脱氢酶的活性。此外，亚硫酸盐降低了MDH的商业解决方案的活性，这是由抗氧化剂和二硫苏糖醇防止。亚硫酸盐还诱导线粒体肿胀，并降低线粒体膜电位，Ca 2+的保留能力，NAD（P）H池和细胞色素c免疫含量时，在培养基中的Ca 2+。钌红，环孢素A（CsA）和ADP阻止这些变化，支持线粒体通透性转换（MPT）参与这些影响。我们进一步观察到，N-乙基马来酰亚胺防止亚硫酸盐引起的肿胀，亚硫酸盐减少脑线粒体中游离巯基含量。这些发现表明亚硫酸盐直接作用于含有硫醇基团的MPT孔。最后，我们验证了亚硫酸盐降低大脑皮层切片中的细胞活力，并且CsA阻止了这种作用。因此，可以推测亚硫酸盐引起的线粒体能量平衡和MPT的紊乱可能参与了SO缺乏所特有的神经元损伤。(C)2014爱思唯尔有限公司版权所有。
Sulfite oxidase (SO) deficiency is biochemically characterized by the accumulation of sulfite, thiosulfate and S-sulfocysteine in tissues and biological fluids of the affected patients. The main clinical symptoms include severe neurological dysfunction and brain abnormalities, whose pathophysiology is still unknown. The present study investigated the in vitro effects of sulfite and thiosulfate on mitochondrial homeostasis in rat brain mitochondria It was verified that sulfite per se, but not thiosulfate, decreased state 3, CCCP-stimulated state and respiratory control ratio in mitochondria respiring with glutamate plus malate. In line with this, we found that sulfite inhibited the activities of glutamate and malate (MDH) dehydrogenases. In addition, sulfite decreased the activity of a commercial solution of MDH, that was prevented by antioxidants and dithiothreitol. Sulfite also induced mitochondrial swelling and reduced mitochondrial membrane potential, Ca2+ retention capacity, NAD(P)H pool and cytochrome c immunocontent when Ca2+ was present in the medium. These alterations were prevented by ruthenium red, cyclosporine A (CsA) and ADP, supporting the involvement of mitochondrial permeability transition (MPT) in these effects. We further observed that N-ethylmaleimide prevented the sulfite-elicited swelling and that sulfite decreased free thiol group content in brain mitochondria. These findings indicate that sulfite acts directly on MPT pore containing thiol groups. Finally, we verified that sulfite reduced cell viability in cerebral cortex slices and that this effect was prevented by CsA. Therefore, it may be presumed that disturbance of mitochondrial energy homeostasis and MPT induced by sulfite could be involved in the neuronal damage characteristic of SO deficiency. (C) 2014 Elsevier B.V. All rights reserved.