Department of Biomedical and Biotechnological Sciences, University of Catania, V.le Andrea Doria 6, 95125 Catania, Italy.
Department of Biomedical and Biotechnological Sciences, University of Catania, Torre Biologica, Via Santa Sofia 97, 95125 Catania, Italy.
Int J Mol Sci. 2020 Oct 22;21(21):7809. doi: 10.3390/ijms21217809.
MPP is the active metabolite of MPTP, a molecule structurally similar to the herbicide Paraquat, known to injure the dopaminergic neurons of the nigrostriatal system in Parkinson's disease models. Within the cells, MPP accumulates in mitochondria where it inhibits complex I of the electron transport chain, resulting in ATP depletion and neuronal impairment/death. So far, MPP is recognized as a valuable tool to mimic dopaminergic degeneration in various cell lines. However, despite a large number of studies, a detailed characterization of mitochondrial respiration in neuronal cells upon MPP treatment is still missing. By using high-resolution respirometry, we deeply investigated oxygen consumption related to each respiratory state in differentiated neuroblastoma cells exposed to the neurotoxin. Our results indicated the presence of extended mitochondrial damage at the inner membrane level, supported by increased LEAK respiration, and a drastic drop in oxygen flow devoted to ADP phosphorylation in respirometry measurements. Furthermore, prior to complex I inhibition, an enhancement of complex II activity was observed, suggesting the occurrence of some compensatory effect. Overall our findings provide a mechanistic insight on the mitochondrial toxicity mediated by MPP, relevant for the standardization of studies that employ this neurotoxin as a disease model.
MPP 是 MPTP 的活性代谢物，MPTP 是一种与除草剂百草枯结构相似的分子，已知会损伤帕金森病模型中的黑质纹状体系统中的多巴胺能神经元。在细胞内，MPP 积聚在线粒体中，在线粒体中它会抑制电子传递链的复合物 I，导致 ATP 耗竭和神经元损伤/死亡。到目前为止，MPP 被认为是模拟各种细胞系中多巴胺能变性的有价值的工具。然而，尽管进行了大量研究，但对于 MPP 处理后神经元细胞中线粒体呼吸的详细特征仍然缺乏了解。通过使用高分辨率呼吸测量法，我们深入研究了暴露于神经毒素的分化神经母细胞瘤细胞中与每个呼吸状态相关的耗氧量。我们的结果表明，在呼吸测量中，存在内膜水平的线粒体损伤扩展，通透性增加，以及用于 ADP 磷酸化的耗氧量急剧下降，这得到了支持。此外，在复合物 I 抑制之前，观察到复合物 II 活性增强，表明发生了一些代偿效应。总的来说，我们的研究结果提供了 MPP 介导的线粒体毒性的机制见解，这对于使用这种神经毒素作为疾病模型的研究的标准化具有重要意义。
