A novel lysosome‐to‐mitochondria signaling pathway disrupted by amyloid‐β oligomers
Open accessAbstract
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.
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Certain Aβ oligomers may, depending on the presence of tau, block mitochondrial activity through lysosomal mTORC1 protein kinase activity but potentially stimulate mitochondrial activity in the absence of tau.
“Recent work has shown that certain Aβ oligomers may, depending on the presence of tau, block mitochondrial activity through lysosomal mTORC1 protein kinase activity but potentially stimulate mitochondrial activity in the absence of tau (42).”
From Molecular subtyping of Alzheimer’s disease using RNA sequencing data reveals novel mechanisms and targets (2021) · cites this paper as [42]
The Results and Discussion (page unavailable) report that Aβ oligomers block nutrient-induced mitochondrial activity through a tau-dependent mechanism. But they attribute the inhibition to mTORC1 activation at the plasma membrane, not at lysosomes. In tau-knockout neurons, mitochondrial activity was insensitive to Aβ oligomers; the paper does not report that the oligomers stimulate it. (LLM, conf=0.90)
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Zhang, J., Zhang, Y., Wang, J., Xia, Y., Zhang, J., & Chen, L. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01911-3 · Cited by 1,138 · see citing works
“…oligomers are the primary neurotoxic substances, 131 – 133 disruption of cell membrane integrity, 134 activation in in fl ammatory responses, 135,136 causes of calcium homeostasis imbalance 137 and mitochondrial dysfunction, 138 – 140 triggers in oxidative stress, 141 and damage factor of synapses.”
BackgroundNeff, R. A., Wang, M., Vatansever, S., Guo, L., Ming, C., Wang, Q., Wang, E., Horgusluoglu-Moloch, E., Song, W.-M., Li, A., et al. (2021) · Science Advances · doi:10.1126/sciadv.abb5398 · Cited by 306 · see citing works
“Recent work has shown that certain A oligomers may, depending on the presence of tau, block mitochondrial activity through lysosomal mTORC1 protein kinase activity but potentially stimulate mitochondrial activity in the absence of tau (42).”
Background
- Authors
- Norambuena, A., Wallrabe, H., Cao, R., Wang, D. B., Silva, A., Svindrych, Z., Periasamy, A., Hu, S., Tanzi, R. E., Kim, D. Y., & Bloom, G. S.
- Affiliations
- University of Virginia (US)
- Harvard University (US)
- Corresponding author
- Norambuena, Andrés
- Bloom, George S
- ORCID
- Venue
- The EMBO Journal
- Published
- 2018-10-22
- Volume
- 37
- Issue
- 22
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC6236329
- OpenAlex
- W2895929116
- Cited by
- 61
- References
- 62
- Citations by year
- 2026: 4 · 2025: 7 · 2024: 5 · 2023: 3 · 2022: 10 · 2021: 8 · 2020: 10 · 2019: 10 · 2018: 4
- FWCI
- 5.50
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The EMBO Journal (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- HHS|National Institutes of Health (RF1 AG051085, RF1 AG048080, R01 AG014713, S10 OD016446, R21 AG052062, P01 AG015379)
- BrightFocus Foundation
- Owens Family Foundation
- Alzheimer's Association (ZEN‐16‐363266)
- Cure Alzheimer's Fund
- Webb and Tate Wilson
- Virginia Chapter of the Lady's Auxilliary of the Fraternal Order of Eagles
- University of Virginia President's Fund for Excellence
- Alzheimer's and Related Diseases Research Award Fund (17‐5)
- Virginia Chapter of the Lady's Auxiliary of the Fraternal Order of Eagles
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Keywords
- mTORC1, amyloid-beta oligomers, Alzheimer's disease, mitochondrial dysfunction, mitochondrial DNA synthesis, NADH, NADPH, cerebral oxygen consumption, tau protein, neurofibrillary tangles, tuberous sclerosis complex, insulin, amino acids
- MeSH terms
- Mechanistic Target of Rapamycin Complex 1, Alzheimer Disease, Animals, Brain, Cell Membrane, Fibroblasts, Humans, Lysosomes, Mitochondria, Tuberous Sclerosis, Signal Transduction, Amyloid beta-Peptides, Mice
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