A novel lysosome-to-mitochondria signaling pathway disrupted by amyloid-β oligomers.

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.

• Authors: Andrés Norambuena, Horst Wallrabe, Rui Cao, Dora Bigler Wang, Antonia Silva, Zdenek Svindrych, Ammasi Periasamy, Song Hu, Rudolph E Tanzi, Doo Yeon Kim, George S Bloom
• Journal: The EMBO journal (EMBO J) Vol. 37 Issue 22 (11 15 2018) ISSN: 1460-2075 [Electronic] England
• PMID: 30348864 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 The Authors.

Chemical References

• Amyloid beta-Peptides
• Mechanistic Target of Rapamycin Complex 1

Topics

• Alzheimer Disease (genetics, metabolism, pathology)
• Amyloid beta-Peptides (genetics, metabolism)
• Animals
• Brain (metabolism, pathology)
• Cell Membrane (genetics, metabolism, pathology)
• Fibroblasts (metabolism, pathology)
• Humans
• Lysosomes (genetics, metabolism, pathology)
• Mechanistic Target of Rapamycin Complex 1 (genetics, metabolism)
• Mice
• Mitochondria (genetics, metabolism, pathology)
• Signal Transduction
• Tuberous Sclerosis (genetics, metabolism, pathology)