Mitochondrial hyperpolarization in iPSC-derived neurons from patients of FTDP-17 with 10+16 MAPT mutation leads to oxidative stress and neurodegeneration.
Mitochondrial hyperpolarization in iPSC-derived neurons from patients of FTDP-17 with 10+16 MAPT mutation leads to oxidative stress and neurodegeneration.
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DOI：
10.1016/j.redox.2017.03.008
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发表时间：
2017-08
期刊：
影响因子：
11.4
通讯作者：
Abramov AY
中科院分区：
文献类型：
--
作者：
Esteras N;Rohrer JD;Hardy J;Wray S;Abramov AY
Tau蛋白内含物是多种神经退行性疾病的常见标志。编码tau的MAPT基因中的10+16内含子突变通过改变基因的剪接并诱导更易于聚集的4 R tau同种型的产生增加而引起与17号染色体（FTDP-17）相关的额颞叶痴呆和帕金森综合征。然而，将增加的4 R tau与神经退行性变联系起来的分子机制还没有很好地理解。在这里，我们使用来自携带10+16突变的FTDP-17患者的iPSC衍生神经元来研究神经变性的分子机制。我们发现，线粒体功能改变的神经元的患者。我们发现，FTDP-17神经元呈现出增加的线粒体膜电位，这部分是由F1 Fo ATP酶以反向模式工作来维持的。10+16 MAPT突变还与较低的线粒体NADH水平、部分抑制的复合物I驱动的呼吸和较低的氧化磷酸化ATP产生相关，细胞依赖糖酵解来维持ATP水平。FTDP-17神经元中线粒体膜电位的增加导致线粒体中ROS的过度产生，这反过来又导致氧化应激和细胞死亡。这些细胞中线粒体ROS的过度产生是神经元细胞死亡的主要触发因素，并且可以通过线粒体抗氧化剂来预防，具有10+16 MAPT突变的iPSC衍生的神经元显示出改变的生物能量学。患者神经元的呼吸受到抑制，但ATP通过糖酵解得到补偿。生物能量的改变可以用呼吸底物来挽救。线粒体膜电位较高，导致氧化应激和细胞死亡。
Tau protein inclusions are a frequent hallmark of a variety of neurodegenerative disorders. The 10+16 intronic mutation in MAPT gene, encoding tau, causes frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), by altering the splicing of the gene and inducing an increase in the production of 4R tau isoforms, which are more prone to aggregation. However, the molecular mechanisms linking increased 4R tau to neurodegeneration are not well understood. Here, we have used iPSC-derived neurons from patients of FTDP-17 carrying the 10+16 mutation to study the molecular mechanisms underlying neurodegeneration. We show that mitochondrial function is altered in the neurons of the patients. We found that FTDP-17 neurons present an increased mitochondrial membrane potential, which is partially maintained by the F1Fo ATPase working in reverse mode. The 10+16 MAPT mutation is also associated with lower mitochondrial NADH levels, partially supressed complex I-driven respiration, and lower ATP production by oxidative phosphorylation, with cells relying on glycolysis to maintain ATP levels. Increased mitochondrial membrane potential in FTDP-17 neurons leads to overproduction of the ROS in mitochondria, which in turn causes oxidative stress and cell death. Mitochondrial ROS overproduction in these cells is a major trigger for neuronal cell death and can be prevented by mitochondrial antioxidants iPSC-derived neurons with 10+16 MAPT mutation show altered bioenergetics. Respiration is inhibited in patients’ neurons, but ATP is compensated by glycolysis. Bioenergetic alterations can be rescued with substrates for respiration. Mitochondrial membrane potential is higher, leading to oxidative stress and cell death.