Medvedev A E, Buneeva O A, Kopylov A T, Tikhonova O V, Medvedeva M V, Nerobkova L N, Kapitsa I G, Zgoda V G
Institute of Biomedical Chemistry, Moscow, 119121, Russia.
Biochemistry (Mosc). 2017 Mar;82(3):330-339. doi: 10.1134/S0006297917030117.
Mitochondria play an important role in molecular mechanisms of neuroplasticity, adaptive changes of the brain that occur in the structure and function of its cells in response to altered physiological conditions or development of pathological disorders. Mitochondria are a crucial target for actions of neurotoxins, causing symptoms of Parkinson's disease in various experimental animal models, and also neuroprotectors. Good evidence exists in the literature that mitochondrial dysfunction induced by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) influences functioning of the ubiquitin-proteasomal system (UPS) responsible for selective proteolytic degradation of proteins from various intracellular compartments (including mitochondria), and neuroprotective effects of certain antiparkinsonian agents (monoamine oxidase inhibitors) may be associated with their effects on UPS. The 19S proteasomal Rpn10 subunit is considered as a ubiquitin receptor responsible for delivery of ubiquitinated proteins to the proteasome proteolytic machinery. In this study, we investigated proteomic profiles of mouse brain mitochondrial Rpn10-binding proteins, brain monoamine oxidase B (MAO B) activity, and their changes induced by a single-dose administration of the neurotoxin MPTP and the neuroprotector isatin. Administration of isatin to mice prevented MPTP-induced inactivation of MAO B and influenced the profile of brain mitochondrial Rpn10-binding proteins, in which two pools of proteins were clearly recognized. The constitutive pool was insensitive to neurotoxic/neuroprotective treatments, while the variable pool was specifically influenced by MPTP and the neuroprotector isatin. Taking into consideration that the neuroprotective dose of isatin used in this study can result in brain isatin concentrations that are proapoptotic for cells in vitro, the altered repertoire of mitochondrial Rpn10-binding proteins may thus represent a part of a switch mechanism from targeted elimination of individual (damaged) proteins to more efficient ("global") elimination of damaged organelles and whole damaged cells.
线粒体在神经可塑性的分子机制中发挥着重要作用。神经可塑性是指大脑细胞的结构和功能在生理条件改变或病理疾病发展时发生的适应性变化。线粒体是神经毒素作用的关键靶点，在各种实验动物模型中可引发帕金森病症状，同时也是神经保护剂的作用靶点。文献中有充分证据表明，神经毒素1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）诱导的线粒体功能障碍会影响泛素-蛋白酶体系统（UPS）的功能，该系统负责选择性地从细胞内各个区室（包括线粒体）中进行蛋白质的水解降解，某些抗帕金森病药物（单胺氧化酶抑制剂）的神经保护作用可能与其对UPS的影响有关。19S蛋白酶体的Rpn10亚基被认为是一种泛素受体，负责将泛素化蛋白质递送至蛋白酶体的蛋白水解机制。在本研究中，我们调查了小鼠脑线粒体Rpn10结合蛋白的蛋白质组学概况、脑单胺氧化酶B（MAO B）活性，以及单次给予神经毒素MPTP和神经保护剂异吲哚酮所引起的变化。给小鼠施用异吲哚酮可预防MPTP诱导的MAO B失活，并影响脑线粒体Rpn10结合蛋白的概况，其中可清晰识别出两类蛋白质组。组成型蛋白质组对神经毒性/神经保护处理不敏感，而可变蛋白质组则受到MPTP和神经保护剂异吲哚酮的特异性影响。考虑到本研究中使用的异吲哚酮神经保护剂量可能导致脑内异吲哚酮浓度在体外对细胞具有促凋亡作用，线粒体Rpn10结合蛋白库的改变可能因此代表了一种转换机制的一部分，即从靶向清除单个（受损）蛋白质转变为更有效地（“整体”）清除受损细胞器和整个受损细胞。
