# Molecular Mechanisms of Organelle-based Metabolic Signaling

> **NIH NIH R35** · UNIVERSITY OF CALIFORNIA BERKELEY · 2024 · $614,394

## Abstract

ABSTRACT
 The molecular mechanisms through which cells sense nutrients remain largely unknown, but their
elucidation is key to our understanding of metabolic regulation both in normal and disease states. At the center
of nutrient sensing and growth regulation is an ancient protein kinase known as the mechanistic Target of
Rapamycin Complex 1 (mTORC1). In response to the combined action of metabolic inputs such as nutrients,
growth factors, energy and oxygen, mTORC1 translocates from the cytoplasm to the surface of lysosomes,
where it becomes activated. Accumulating evidence indicates that aberrant mTORC1 activation at the lysosome
could be a driving force in diseases ranging from cancer to type-2 diabetes to neurodegeneration. Thus, a deep
mechanistic understanding of how mTORC1 is activated and then inactivated in response to nutrients could point
the way to novel therapeutic strategies in these diseases. My lab has made important contributions to the
understanding of mTORC1 pathway organization, and how its function is integrated with the many activities of
the lysosome. In particular, we have identified a dedicated signaling pathway via which cholesterol, an important
building block for cellular membranes, promotes mTORC1 recruitment to the lysosome and activation of its
downstream programs. We have uncovered membrane contact sites between lysosomes and the endoplasmic
reticulum as key nodes where mTORC1 activation by cholesterol occurs, thus implicating inter-organelle
communication as an important aspect of mTORC1 regulation. Furthermore, we found that excess mTORC1
signaling, caused by cholesterol accumulation in the lysosome, drives cellular dysfunction and could be a driving
force in a neurodegenerative and metabolic disease, Niemann-Pick type C (NPC).
 These discoveries directly lead to deep questions on the organization of cellular nutrient sensing, which
are at the core of the current MIRA proposal. One key challenge is to elucidate the mechanisms and physiological
roles of lipid-dependent mTORC1 regulation, specifically whether dedicated cholesterol sensors exist in the
lysosomal membrane, and how they couple the abundance of sterol molecules to mTORC1 activation and to
overall metabolic regulation at the cell and organism level. Based on our finding that cholesterol sensing by
mTORC1 involves physical communication between the lysosome and the ER, another major goal of the
proposal is to delineate the machinery that mediates communication and metabolite exchange between the
lysosome and the ER, and how this machinery participates in regulation of mTORC1 as well as another major
metabolic kinase, protein kinase A. Finally, the pathogenic role of dysregulated mTORC1 in NPC, and the ability
of mTORC1 inhibition to restore several parameters of NPC cell function, strongly support mTORC1 as a prime
target in neurodegenerative disease. We will thus determine how lysosomal mTORC1 controls neuronal cell
homeostasis, and how dysregulated mTOR...

## Key facts

- **NIH application ID:** 10814948
- **Project number:** 5R35GM149302-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA BERKELEY
- **Principal Investigator:** Roberto Zoncu
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $614,394
- **Award type:** 5
- **Project period:** 2023-05-01 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10814948

## Citation

> US National Institutes of Health, RePORTER application 10814948, Molecular Mechanisms of Organelle-based Metabolic Signaling (5R35GM149302-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10814948. Licensed CC0.

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