Selective vulnerability of synaptic signaling and metabolism to nitrosative stress.
Selective vulnerability of synaptic signaling and metabolism to nitrosative stress.
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DOI：
10.1089/ars.2012.4559
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发表时间：
2012-08
影响因子：
6.6
通讯作者：
A. A. Mongin-A.;Preeti Dohare;D. Jourd’heuil
中科院分区：
文献类型：
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作者：
A. A. Mongin-A.;Preeti Dohare;D. Jourd’heuil
意义一氧化氮(NO)在中枢神经系统中扮演着不同的生理角色，在那里它调节神经元通讯，调节血流，并参与先天性免疫反应。在许多脑部疾病中，NO的过量产生还会导致活性和毒性中间产物的形成，这些中间产物通常被称为活性氮物种(RNS)。RNS对脑细胞造成不可逆或不可逆的损害。该领域的最新进展最近的工作集中在NO和RNS产生蛋白质修饰的能力上，包括半胱氨酸残基的S亚硝化，在许多情况下，这会影响细胞功能和生存能力。关键问题绝大多数神经病理学研究的重点是细胞活性的丧失，但亚硝化应激也可能严重损害神经元突起的功能：轴突投射和树突树。轴突和树突的功能完整性在很大程度上依赖于局部代谢和代谢酶及细胞器的有效传递。本文综述了亚硝酸盐胁迫对能量代谢的主要途径：糖酵解、三羧酸循环和线粒体呼吸的影响，重点介绍了蛋白质硫醇的修饰。未来方向我们认为，轴突和树突在亚硝化胁迫下非常脆弱，这是因为它们的糖酵解能力低，并且高度依赖于代谢酶和细胞器从细胞体及时递送。因此，补充糖酵解的最终产物丙酮酸或乳酸，可能有助于保护远端神经元突起的新陈代谢，保护或恢复患病大脑的突触功能。
SIGNIFICANCE Nitric oxide (NO) plays diverse physiological roles in the central nervous system, where it modulates neuronal communication, regulates blood flow, and contributes to the innate immune responses. In a number of brain pathologies, the excessive production of NO also leads to the formation of reactive and toxic intermediates generically termed reactive nitrogen species (RNS). RNS cause irreversible or poorly reversible damage to brain cells. RECENT ADVANCES Recent work in the field focused on the ability of NO and RNS to yield protein modifications, including the S-nitrosation of cysteine residues, which, in many instances, impact cellular functions and viability. CRITICAL ISSUES The vast majority of neuropathological studies focus on the loss of cell viability, but nitrosative stress may also strongly impair the functions of neuronal processes: axonal projections and dendritic trees. The functional integrity of axons and dendrites critically depends on local metabolism and effective delivery of metabolic enzymes and organelles. Here, we summarize the existing literature describing the effects of nitrosative stress on the major pathways of energetic metabolism: glycolysis, tricarboxylic acid cycle, and mitochondrial respiration, with the emphasis on modifications of protein thiols. FUTURE DIRECTIONS We propose that axons and dendrites are highly vulnerable to nitrosative stress because of their low glycolytic capacity and high dependence on timely delivery of metabolic enzymes and organelles from the cell body. Thus, supplementation with the end products of glycolysis, pyruvate or lactate, may help preserve metabolism in distal neuronal processes and protect or restore synaptic function in the ailing brain.