Chen Fannie W, Davies Joanna P, Calvo Raul, Chaudhari Jagruti, Dolios Georgia, Taylor Mercedes K, Patnaik Samarjit, Dehdashti Jean, Mull Rebecca, Dranchack Patricia, Wang Amy, Xu Xin, Hughes Emma, Southall Noel, Ferrer Marc, Wang Rong, Marugan Juan J, Ioannou Yiannis A
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Early Translation Branch, National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, USA.
iScience. 2022 Aug 14;25(9):104941. doi: 10.1016/j.isci.2022.104941. eCollection 2022 Sep 16.
Numerous studies have established the involvement of lysosomal and mitochondrial dysfunction in the pathogenesis of neurodegenerative disorders such as Alzheimer's and Parkinson diseases. Building on our previous studies of the neurodegenerative lysosomal lipidosis Niemann-Pick C1 (NPC1), we have unexpectedly discovered that activation of the mitochondrial chaperone tumor necrosis factor receptor-associated protein 1 (TRAP1) leads to the correction of the lysosomal storage phenotype in patient cells from multiple lysosomal storage disorders including NPC1. Using small compound activators specific for TRAP1, we find that activation of this chaperone leads to a generalized restoration of lysosomal and mitochondrial health. Mechanistically, we show that this process includes inhibition of oxidative phosphorylation and reduction of oxidative stress, which results in activation of AMPK and ultimately stimulates lysosome recycling. Thus, TRAP1 participates in lysosomal-mitochondrial crosstalk to maintain cellular homeostasis and could represent a potential therapeutic target for multiple disorders.
众多研究已证实溶酶体和线粒体功能障碍参与了诸如阿尔茨海默病和帕金森病等神经退行性疾病的发病机制。基于我们之前对神经退行性溶酶体脂质贮积病尼曼-匹克C1型（NPC1）的研究，我们意外地发现线粒体伴侣肿瘤坏死因子受体相关蛋白1（TRAP1）的激活可纠正来自包括NPC1在内的多种溶酶体贮积症患者细胞中的溶酶体贮积表型。使用对TRAP1特异的小分子化合物激活剂，我们发现该伴侣蛋白的激活可导致溶酶体和线粒体健康的普遍恢复。从机制上来说，我们表明这一过程包括抑制氧化磷酸化和降低氧化应激，从而导致AMPK激活并最终刺激溶酶体再循环。因此，TRAP1参与溶酶体-线粒体相互作用以维持细胞稳态，并可能成为多种疾病的潜在治疗靶点。
