A novel lysosome-to-mitochondria signaling pathway disrupted by amyloid-β oligomers
A novel lysosome-to-mitochondria signaling pathway disrupted by amyloid-β oligomers
复制标题
一种新的溶酶体到线粒体的信号通路被淀粉样蛋白-β低聚物破坏
DOI：
10.15252/embj.2018100241
复制
发表时间：
2018-11-15
期刊：
影响因子：
11.4
通讯作者：
Bloom, George S.
中科院分区：
文献类型：
--
作者：
Norambuena, Andres;Wallrabe, Horst;Bloom, George S.
The mechanisms of mitochondrial dysfunction in Alzheimer's disease are incompletely understood. Using two-photon fluorescence lifetime microscopy of the coenzymes, NADH and NADPH, and tracking brain oxygen metabolism with multi-parametric photoacoustic microscopy, we show that activation of lysosomal mechanistic target of rapamycin complex 1 (mTORC1) by insulin or amino acids stimulates mitochondrial activity and regulates mitochondrial DNA synthesis in neurons. Amyloid-beta oligomers, which are precursors of amyloid plaques in Alzheimer's disease brain and stimulate mTORC1 protein kinase activity at the plasma membrane but not at lysosomes, block this Nutrient-induced Mitochondrial Activity (NiMA) by a mechanism dependent on tau, which forms neurofibrillary tangles in Alzheimer's disease brain. NiMA was also disrupted in fibroblasts derived from two patients with tuberous sclerosis complex, a genetic disorder that causes dysregulation of lysosomal mTORC1. Thus, lysosomal mTORC1 couples nutrient availability to mitochondrial activity and links mitochondrial dysfunction to Alzheimer's disease by a mechanism dependent on the soluble building blocks of the poorly soluble plaques and tangles.
