Dopamine and Methamphetamine Differentially Affect Electron Transport Chain Complexes and Parkin in Rat Striatum: New Insight into Methamphetamine Neurotoxicity.
Dopamine and Methamphetamine Differentially Affect Electron Transport Chain Complexes and Parkin in Rat Striatum: New Insight into Methamphetamine Neurotoxicity.
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DOI：
10.3390/ijms23010363
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发表时间：
2021-12-29
影响因子：
5.6
通讯作者：
Moszczynska A
中科院分区：
文献类型：
--
作者：
Bazylianska V;Sharma A;Chauhan H;Schneider B;Moszczynska A
甲基苯丙胺是一种高度滥用的精神刺激剂，对纹状体中的多巴胺能神经末梢具有神经毒性，并增加患帕金森病(PD)的风险。在体内，冰毒介导的DA释放，以及随后的DA介导的突触前和突触后神经元的氧化应激和线粒体功能障碍，介导了冰毒的神经毒性。冰毒引发的氧化应激损伤Parkin，Parkin是一种神经保护蛋白，通过参与线粒体的维护参与帕金森病的病因。目前尚不清楚冰毒本身是否导致线粒体功能障碍，以及parkin是否调节复合体I，这是一种在帕金森病中下调的酶复合体。为了确定这一点，我们分别评估了冰毒或DA单独对分离的纹状体线粒体电子传输链(ETC)复合体和蛋白质Parkin的影响。在我们的制剂中，METH降低了选定的复合体I、II和III亚单位(分别为NDUFS3、SDHA和UQCRC2)的水平，而DA仅降低了NDUFS3亚单位的水平。我们还表明，在类似的实验条件下，突触体线粒体内选定的亚基并没有减少。最后，我们发现parkin过表达并不影响大鼠纹状体中NDUFS3亚单位的水平。这些结果表明，冰毒本身是促进纹状体线粒体功能障碍的一个因素，因此，它是一种潜在的抗冰毒药物靶点。观察到的ETC复合体亚基的减少表明，DA和METH通过对其亚单位的氧化损伤降低了ETC复合体的活性，突触体线粒可能比核周线粒体对DA和METH诱导的线粒体ETC复合体的破坏具有一定的抵抗力。结果还表明，parkin对大鼠纹状体NDUFS3的转化没有调节作用。
Methamphetamine (METH) is a highly abused psychostimulant that is neurotoxic to dopaminergic (DAergic) nerve terminals in the striatum and increases the risk of developing Parkinson’s disease (PD). In vivo, METH-mediated DA release, followed by DA-mediated oxidative stress and mitochondrial dysfunction in pre- and postsynaptic neurons, mediates METH neurotoxicity. METH-triggered oxidative stress damages parkin, a neuroprotective protein involved in PD etiology via its involvement in the maintenance of mitochondria. It is not known whether METH itself contributes to mitochondrial dysfunction and whether parkin regulates complex I, an enzymatic complex downregulated in PD. To determine this, we separately assessed the effects of METH or DA alone on electron transport chain (ETC) complexes and the protein parkin in isolated striatal mitochondria. We show that METH decreases the levels of selected complex I, II, and III subunits (NDUFS3, SDHA, and UQCRC2, respectively), whereas DA decreases the levels only of the NDUFS3 subunit in our preparations. We also show that the selected subunits are not decreased in synaptosomal mitochondria under similar experimental conditions. Finally, we found that parkin overexpression does not influence the levels of the NDUFS3 subunit in rat striatum. The presented results indicate that METH itself is a factor promoting dysfunction of striatal mitochondria; therefore, it is a potential drug target against METH neurotoxicity. The observed decreases in ETC complex subunits suggest that DA and METH decrease activities of the ETC complexes via oxidative damage to their subunits and that synaptosomal mitochondria may be somewhat “resistant” to DA- and METH-induced disruption in mitochondrial ETC complexes than perikaryal mitochondria. The results also suggest that parkin does not regulate NDUFS3 turnover in rat striatum.
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DOI：
10.1017/s1461145708009802
发表时间：
2009-07
期刊：
The international journal of neuropsychopharmacology
影响因子：
--
作者：
Bachmann RF;Wang Y;Yuan P;Zhou R;Li X;Alesci S;Du J;Manji HK
通讯作者：
Manji HK
影响因子：
1.7
作者：
Choi, P;Ostrerova-Golts, N;Wolozin, B
通讯作者：
Wolozin, B
影响因子：
4.3
作者：
Clarke, Kieran J.;Adams, Alison E.;Porter, Richard K.
通讯作者：
Porter, Richard K.
影响因子：
4.3
作者：
Gautam, Alpa H.;Zeevalk, Gail D.
通讯作者：
Zeevalk, Gail D.
影响因子：
3.6
作者：
Feier, Gustavo;Valvassori, Samira S.;Quevedo, Joao
通讯作者：
Quevedo, Joao