# Mechanisms of autophagy and mTOR signaling

> **NIH NIH R35** · UNIVERSITY OF MINNESOTA · 2024 · $417,458

## Abstract

The protein kinase mTOR (mechanistic target of rapamycin) pathways play crucial roles in regulating cell
growth, survival, and metabolism in response to changes in cellular energy and nutrient status. Despite
significant efforts, our understanding of mTOR pathways still has many gaps that need to be filled. To
address the knowledge gaps, our research will focus on three directions. Firstly, we will investigate the
mechanisms by which mTOR controls the initiation and termination of autophagy. Although our knowledge
in this area has significantly improved, we still do not clearly understand how post-translational modifications,
interactions, and translocations of autophagy regulators are coordinated to drive autophagy initiation.
Furthermore, while mTOR regulates autophagy termination, the underlying mechanisms remain elusive.
Secondly, we will investigate how cells decide between autophagy, mitophagy, and apoptosis during energy
crisis caused by mitochondrial dysfunction. Our recent study has challenged the long-held notion that
autophagy is responsible for supplying energy to energy-deprived cells for survival. Contrary to the prevailing
concept, we found that energy-deprived cells restrain autophagy and mitophagy via activating AMPK, the
major energy sensor kinase in mammalian cells. Our research has revealed previously unrecognized roles
of ULK1, the central kinase that regulates autophagy downstream of mTOR, in the crosstalk between
autophagy, mitochondria, and apoptosis. This finding highlights the critical importance of maintaining
functional mitochondria for autophagy. Investigating the coordination mechanism underlying the crosstalk
between autophagy, mitophagy, and apoptosis during energy stress is crucial for a comprehensive
understanding of cellular energetics for cell survival. Thirdly, we will investigate the functions of mTOR in
different cellular compartments. The majority of previous studies have focused on lysosomal mTOR, with
limited explanation of how lysosomal mTOR controls protein synthesis and autophagy initiation that primarily
occur in the endoplasmic reticulum. While non-lysosomal functions of mTOR have recently emerged, their
roles in different cellular compartments remain largely unexplored. Through our single-molecule analysis,
we have learned that the majority of mTOR exists in non-lysosomal compartments and that some forms of
non-lysosomal mTOR are responsive to amino acids, providing unprecedented insights into mTOR
distribution and regulation in various cellular locations. Addressing this critical knowledge gap is essential
for elucidating previously unrecognized functions of mTOR. Through these three directions of research, our
study aims to advance fundamental knowledge on mTOR functions in coordinating nutrient, growth, and
energy status with autophagy, mitophagy, and cell survival. Additionally, the outcomes of this study are
expected to provide crucial insights into the cellular pathways for energy sensing and ...

## Key facts

- **NIH application ID:** 10841983
- **Project number:** 2R35GM130353-06
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Do-Hyung Kim
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $417,458
- **Award type:** 2
- **Project period:** 2019-03-08 → 2029-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10841983

## Citation

> US National Institutes of Health, RePORTER application 10841983, Mechanisms of autophagy and mTOR signaling (2R35GM130353-06). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10841983. Licensed CC0.

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