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Nutrient-induced Mitochondrial Activation (NiMA): A Novel Lysosome-to-Mitochondria Signaling Pathway Disrupted by Amyloid-β Oligomers

44 Pages Posted: 8 Jun 2018 Sneak Peek Status: Review Complete

See all articles by Andrés Norambuena

Andrés Norambuena

University of Virginia - Biology Department

Horst Wallrabe

University of Virginia - Biology Department

Rui Cao

University of Virginia - Department of Biomedical Engineering

Dora Bigler Wang

University of Virginia - Biology Department

Antonia Silva

University of Virginia - Biology Department

Zdenek Svindrych

University of Virginia - Biology Department

Ammasi Periasamy

University of Virginia - Biology Department

Song Hu

University of Virginia - Department of Biomedical Engineering

Doo Yeon Kim

Harvard University - Genetics and Aging Research Unit

Rudolph E. Tanzi

Harvard University - Genetics and Aging Research Unit

George S. Bloom

University of Virginia - Biology Department

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Abstract

The mechanisms of mitochondrial dysfunction in Alzheimer’s Disease (AD) are incompletely understood. Using two-photon fluorescence lifetime microscopy of NAD(P)H 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 AD 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 AD brain. NiMA was also disrupted in fibroblasts derived from a patient 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 AD by a mechanism dependent on soluble building blocks of plaques and tangles.

Suggested Citation

Norambuena, Andrés and Wallrabe, Horst and Cao, Rui and Wang, Dora Bigler and Silva, Antonia and Svindrych, Zdenek and Periasamy, Ammasi and Hu, Song and Kim, Doo Yeon and Tanzi, Rudolph E. and Bloom, George S., Nutrient-induced Mitochondrial Activation (NiMA): A Novel Lysosome-to-Mitochondria Signaling Pathway Disrupted by Amyloid-β Oligomers (2018). Available at SSRN: https://ssrn.com/abstract=3188445 or http://dx.doi.org/10.2139/ssrn.3188445
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Andrés Norambuena

University of Virginia - Biology Department ( email )

Gilmer Hall
McCormick Road
Charlottesville, VA 22904
United States

Horst Wallrabe

University of Virginia - Biology Department

Gilmer Hall
McCormick Road
Charlottesville, VA 22904
United States

Rui Cao

University of Virginia - Department of Biomedical Engineering

Box 400246
Charlottesville, VA 22904-0246
United States

Dora Bigler Wang

University of Virginia - Biology Department

Gilmer Hall
McCormick Road
Charlottesville, VA 22904
United States

Antonia Silva

University of Virginia - Biology Department

Gilmer Hall
McCormick Road
Charlottesville, VA 22904
United States

Zdenek Svindrych

University of Virginia - Biology Department

Gilmer Hall
McCormick Road
Charlottesville, VA 22904
United States

Ammasi Periasamy

University of Virginia - Biology Department

Gilmer Hall
McCormick Road
Charlottesville, VA 22904
United States

Song Hu

University of Virginia - Department of Biomedical Engineering

Box 400246
Charlottesville, VA 22904-0246
United States

Doo Yeon Kim

Harvard University - Genetics and Aging Research Unit

Charlestown, MA
United States

Rudolph E. Tanzi

Harvard University - Genetics and Aging Research Unit ( email )

Charlestown, MA
United States

George S. Bloom (Contact Author)

University of Virginia - Biology Department ( email )

Gilmer Hall
McCormick Road
Charlottesville, VA 22904
United States