Mor Danielle E, Murphy Coleen T
Department of Molecular Biology & LSI Genomics, Princeton University, Princeton, NJ, 08544, USA.
Transl Med Aging. 2020;4:117-120. doi: 10.1016/j.tma.2020.07.007. Epub 2020 Aug 12.
Mitochondrial dysfunction is thought to contribute to neurodegeneration in Parkinson's disease (PD), yet the cellular events that lead to mitochondrial disruption remain unclear. Post-mortem studies of PD patient brains and the use of complex I inhibitors to model the disease previously suggested a reduction in mitochondrial activity as a causative factor in PD, but this may represent an endpoint in the disease process. In our recent studies, we identified a novel link between branched-chain amino acid metabolism and PD, and uncovered mitochondrial hyperactivity as a potential alternative mechanism of PD pathogenesis. Increased mitochondrial activity may occur in a subset of PD patients, or may be a more common early event that precedes the ultimate loss of mitochondrial function. Therefore, it may be that any imbalance in mitochondrial activity, either increased or decreased, could cause a loss of mitochondrial homeostasis that leads to disease. An effective therapeutic strategy may be to target specific imbalances in activity at selective stages of PD or in specific patients, with any efforts to reduce mitochondrial activity constituting a surprising new avenue for PD treatment.
线粒体功能障碍被认为与帕金森病（PD）中的神经退行性变有关，然而导致线粒体破坏的细胞事件仍不清楚。对PD患者大脑的尸检研究以及使用复合物I抑制剂来模拟该疾病，此前提示线粒体活性降低是PD的一个致病因素，但这可能代表疾病过程中的一个终点。在我们最近的研究中，我们发现了支链氨基酸代谢与PD之间的一种新联系，并揭示线粒体活性亢进是PD发病机制的一种潜在替代机制。线粒体活性增加可能发生在一部分PD患者中，或者可能是线粒体功能最终丧失之前更常见的早期事件。因此，可能是线粒体活性的任何失衡，无论是增加还是减少，都可能导致线粒体稳态丧失从而引发疾病。一种有效的治疗策略可能是在PD的特定阶段或特定患者中针对活性的特定失衡，任何降低线粒体活性的努力都构成了一条令人惊讶的PD治疗新途径。
