Metformin reverses TRAP1 mutation-associated alterations in mitochondrial function in Parkinson's disease
Metformin reverses TRAP1 mutation-associated alterations in mitochondrial function in Parkinson's disease
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DOI：
10.1093/brain/awx202
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发表时间：
2017-09-01
期刊：
影响因子：
14.5
通讯作者：
Krueger, Rejko
中科院分区：
文献类型：
--
作者：
Fitzgerald, Julia C.;Zimprich, Alexander;Krueger, Rejko
线粒体蛋白TRAP1和HTRA2先前已被证明在帕金森病激酶PINK1存在下被磷酸化，但下游信号传导是未知的。HTRA2和PINK1功能丧失导致人类和动物的帕金森综合征。在这里，我们确定TRAP1作为HTRA2的相互作用使用无偏质谱法。在我们的人类细胞模型中，TRAP1过表达具有保护作用，挽救了HTRA2和PINK1相关的线粒体功能障碍，并表明TRAP1在HTRA2和PINK1的下游起作用。HTRA2调节TRAP1蛋白水平，但TRAP1不是HTRA2蛋白酶活性的直接靶标。在对帕金森病患者和健康对照进行遗传筛查后，我们还报告了第一个TRAP1突变，导致迟发性帕金森病患者的功能蛋白完全丧失。来自患者的成纤维细胞的分析显示，与健康个体相比，耗氧量、ATP输出和活性氧增加。这与游离NADH池增加、线粒体生物发生增加、触发线粒体未折叠蛋白反应、线粒体膜电位损失以及对线粒体去除和细胞凋亡的敏感性相结合。这些数据突出了TRAP1在能量代谢和线粒体质量控制的调节中的作用。有趣的是，糖尿病药物二甲双胍逆转了能量代谢、线粒体生物发生的突变相关改变，并恢复了线粒体膜电位。总之，我们的数据表明，TRAP1作用于PINK1和HTRA2的下游进行线粒体微调，而TRAP1功能丧失导致能量代谢控制降低，最终影响线粒体膜电位。这些发现为帕金森病的线粒体病理提供了新的见解，并为靶向治疗提供了新的前景。
The mitochondrial proteins TRAP1 and HTRA2 have previously been shown to be phosphorylated in the presence of the Parkinson's disease kinase PINK1 but the downstream signalling is unknown. HTRA2 and PINK1 loss of function causes parkinsonism in humans and animals. Here, we identified TRAP1 as an interactor of HTRA2 using an unbiased mass spectrometry approach. In our human cell models, TRAP1 overexpression is protective, rescuing HTRA2 and PINK1-associated mitochondrial dysfunction and suggesting that TRAP1 acts downstream of HTRA2 and PINK1. HTRA2 regulates TRAP1 protein levels, but TRAP1 is not a direct target of HTRA2 protease activity. Following genetic screening of Parkinson's disease patients and healthy controls, we also report the first TRAP1 mutation leading to complete loss of functional protein in a patient with late onset Parkinson's disease. Analysis of fibroblasts derived from the patient reveal that oxygen consumption, ATP output and reactive oxygen species are increased compared to healthy individuals. This is coupled with an increased pool of free NADH, increased mitochondrial biogenesis, triggering of the mitochondrial unfolded protein response, loss of mitochondrial membrane potential and sensitivity to mitochondrial removal and apoptosis. These data highlight the role of TRAP1 in the regulation of energy metabolism and mitochondrial quality control. Interestingly, the diabetes drug metformin reverses mutation-associated alterations on energy metabolism, mitochondrial biogenesis and restores mitochondrial membrane potential. In summary, our data show that TRAP1 acts downstream of PINK1 and HTRA2 for mitochondrial fine tuning, whereas TRAP1 loss of function leads to reduced control of energy metabolism, ultimately impacting mitochondrial membrane potential. These findings offer new insight into mitochondrial pathologies in Parkinson's disease and provide new prospects for targeted therapies.