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A novel lysosome‐to‐mitochondria signaling pathway disrupted by amyloid‐β oligomers
Author(s) -
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
Publication year - 2018
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.2018100241
Subject(s) - biology , lysosome , microbiology and biotechnology , amyloid (mycology) , mitochondrion , signal transduction , biochemistry , enzyme , botany
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 ( mTORC 1) 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 mTORC 1 protein kinase activity at the plasma membrane but not at lysosomes, block this Nutrient‐induced Mitochondrial Activity (Ni MA ) by a mechanism dependent on tau, which forms neurofibrillary tangles in Alzheimer's disease brain. Ni MA was also disrupted in fibroblasts derived from two patients with tuberous sclerosis complex, a genetic disorder that causes dysregulation of lysosomal mTORC 1. Thus, lysosomal mTORC 1 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.