# Nutrient-Induced Mitochondrial Activity (NiMA): A Novel Lysosome to Mitochondria Signaling Pathway, its mechanisms and role in Alzheimer's Disease

> **NIH NIH R01** · UNIVERSITY OF VIRGINIA · 2021 · $697,844

## Abstract

Alzheimer’s disease (AD) is an aging-related neurodegenerative disorder that affects ~5.8 million people in the
United States. Despite intensive research efforts in recent decades, neither an effective palliative treatment nor
a cure is available, largely due to our limited understanding of the molecular mechanisms that are disrupted in
this devastating disease. Current research suggests that the gradual cognitive decline in AD occurs by the
concurrent deleterious action of soluble amyloid-beta (Aβ) oligomers (AβOs) and intracellular tau in the brain.
Emerging evidence, however, suggests that development of AD may also be attributed to a progressive
deterioration of mitochondrial functioning in brain cells, especially neurons. Besides, AD development has
recently been linked to a progressive impairment in brain’s ability to respond to hormones such as insulin—a
condition known as brain insulin resistance. To investigate these emerging but still elusive molecular
mechanisms of AD, we ask the question: is there any connection between AβOs accumulation, tau,
compromised mitochondrial energy metabolism, and increased insulin resistance in the AD brain and if so, how?
It is known that AβOs interact with the neuronal plasma membrane, which may interrupt communications
between neurons and their environment and disrupt their normal functions. We are particularly interested in how
the AβOs disrupts neuron’s ability to properly respond to the presence of insulin or nutrients and how it affects
ATP production and other mitochondrial functions. Along this direction, we recently discovered Nutrient-Induced
Mitochondrial Activity (NiMA), a novel communication pathway between the lysosome and mitochondria, which
is mediated by the lysosome-associated mechanistic target of rapamycin complex 1 (mTORC1). Interestingly,
the abnormal accumulation of AβOs in AD cellular models disrupted NiMA in a tau-dependent manner. In this
project, we aim to elucidate molecular mechanisms mediating NiMA and to understand how this pathway is
disrupted by AβOs and tau in AD, by screening regulator of this pathway in human neurons in culture and using
two-photon fluorescence lifetime imaging microscopy and state-of-the-art mitochondrial and metabolic imaging
of the mouse brain in vivo. Successful completion of this project not only will advance our understanding of these
earliest steps occurred in AD progression, but also may lead to new therapeutic strategies that could help us
cure this disease.

## Key facts

- **NIH application ID:** 10136503
- **Project number:** 5R01AG067048-02
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Andres M Norambuena
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $697,844
- **Award type:** 5
- **Project period:** 2020-04-15 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10136503

## Citation

> US National Institutes of Health, RePORTER application 10136503, Nutrient-Induced Mitochondrial Activity (NiMA): A Novel Lysosome to Mitochondria Signaling Pathway, its mechanisms and role in Alzheimer's Disease (5R01AG067048-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10136503. Licensed CC0.

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