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Metformin reverses TRAP1 mutation-associated alterations in mitochondrial function in Parkinson’s disease
Brain ( IF 14.5 ) Pub Date : 2017-08-24 , DOI: 10.1093/brain/awx202
Julia C Fitzgerald 1 , Alexander Zimprich 2 , Daniel A Carvajal Berrio 3 , Kevin M Schindler 1, 4 , Brigitte Maurer 1 , Claudia Schulte 1 , Christine Bus 1 , Anne-Kathrin Hauser 1 , Manuela Kübler 1 , Rahel Lewin 1 , Dheeraj Reddy Bobbili 5 , Lisa M Schwarz 1, 6 , Evangelia Vartholomaiou 7 , Kathrin Brockmann 1 , Richard Wüst 1, 8 , Johannes Madlung 9 , Alfred Nordheim 10 , Olaf Riess 11 , L Miguel Martins 12 , Enrico Glaab 5 , Patrick May 5 , Katja Schenke-Layland 3, 13, 14 , Didier Picard 7 , Manu Sharma 15 , Thomas Gasser 1 , Rejko Krüger 1, 5, 16
Affiliation  

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.

中文翻译:

二甲双胍可逆转帕金森病中与 TRAP1 突变相关的线粒体功能改变

线粒体蛋白 TRAP1 和 HTRA2 先前已被证明在帕金森病激酶 PINK1 存在的情况下被磷酸化,但下游信号传导尚不清楚。HTRA2 和 PINK1 功能丧失会导致人类和动物出现帕金森症。在这里,我们使用无偏质谱方法将 TRAP1 鉴定为 HTRA2 的相互作用物。在我们的人类细胞模型中,TRAP1 过表达具有保护作用,可以挽救 HTRA2 和 PINK1 相关的线粒体功能障碍,并表明 TRAP1 作用于 HTRA2 和 PINK1 的下游。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基因筛查后,我们还报告了第一个TRAP1导致迟发性帕金森病患者功能蛋白完全丧失的突变。对源自患者的成纤维细胞的分析表明,与健康个体相比,耗氧量、ATP 输出和活性氧种类增加。这与游离 NADH 池的增加、线粒体生物合成的增加、线粒体未折叠蛋白反应的触发、线粒体膜电位的丧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 在调节能量代谢和线粒体质量控制中的作用。有趣的是,糖尿病药物二甲双胍可逆转能量代谢、线粒体生物发生的突变相关改变并恢复线粒体膜电位。总之,我们的数据显示,TRAP1 在 PINK1 和 HTRA2 的下游作用于线粒体微调,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学提供了新的见解,并为靶向治疗提供了新的前景。
更新日期:2017-08-24
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