A novel lysosome‐to‐mitochondria signaling pathway disrupted by amyloid‐β oligomers. (22nd October 2018)

• Record Type: Journal Article
• Authors: Norambuena, Andrés; Wallrabe, Horst; Cao, Rui; Wang, Dora Bigler; Silva, Antonia; Svindrych, Zdenek; Periasamy, Ammasi; Hu, Song; Tanzi, Rudolph E; Kim, Doo Yeon; Bloom, George S
• Is Part Of: EMBO journal. Volume 37:Number 22(2018)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2018-10-22
• Subjects: Alzheimer's disease -- amyloid‐β oligomers -- mitochondria -- mTOR -- tau; Molecular biology -- Periodicals; 572.805
• DOI: 10.15252/embj.2018100241
• Languages: English
• ISSNs: 0261-4189

Abstract

Abstract: 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‐β 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. Synopsis: Nutrient‐induced Mitochondrial Activation (NiMA) stimulates mitochondrial DNA synthesis through lysosomal mTORC1 and is blocked by amyloid‐β oligomers in tau‐dependent manner. This provides new insight into how impaired energy metabolism and mitochondrial activity contribute to the pathogenesis of Alzheimer's disease. Activation of lysosome‐associated mTORC1 stimulates mitochondrial activity. NiMA is independent of mTORC1‐mediated mRNA translation and mTOR association with mitochondria. Amyloid‐β oligomers (AβOs) block NiMA in a soluble tau‐dependent manner. AβO‐mediated inhibition of NiMA is prevented by forcing mTORC1 localization or activity to lysosomes. NiMA is disrupted in fibroblasts from tuberous sclerosis patients. Abstract : Activation of lysosomal mTORC1 by nutrients induces mitochondrial DNA synthesis in neurons and is inhibited by amyloid‐β oligomers in a tau‐dependent manner.