# Peripheral lysosome levels dictate mTORC1 inactivation even when catabolically impaired

## TL;DR

This study shows that peripheral lysosomes help maintain mTORC1 activity during nutrient scarcity, even when their catabolic functions are impaired.

## Contribution

The study reveals that peripheral lysosome levels, not autophagy, sustain mTORC1 signaling during starvation by modulating PI3K/Akt inputs.

## Key findings

- Peripheral lysosomes remain active during starvation and sustain mTORC1 signaling.
- Lysosome translocation to the perinuclear region is required for mTORC1 suppression.
- mTORC1 signaling persists even when lysosomal catabolism is blocked by chloroquine or concanamycin A.

## Abstract

The mechanistic target of rapamycin complex 1 (mTORC1) is a central driver of cell growth that is frequently hyperactivated in cancer. While mTORC1 is activated at the lysosomal surface in response to growth factors and amino acids, the processes governing its inactivation are not fully understood. Here, we report that sustained mTORC1 suppression during leucine or arginine starvation requires the translocation of peripheral lysosomes to the perinuclear region. Our data suggest that a pool of mTOR remains active at peripheral lysosomes during starvation, and that increased spatial separation between lysosomes and the plasma membrane attenuates PI3K/Akt signaling—thereby reducing inputs that otherwise maintain mTORC1 activity. Consequently, preventing lysosome translocation and increasing peripheral lysosome levels sustains mTORC1 signaling during prolonged starvation in a PI3K/Akt-dependent manner independently of autophagy. Under these conditions, mTORC1 signaling persists even when lysosomal catabolism is perturbed by chloroquine or concanamycin A. Collectively, these data indicate that the peripheral lysosome pool, even when catabolically impaired, can sustain mTORC1 signaling under nutrient scarcity, by modulating PI3K/Akt signaling input to the pathway. These observations identify peripheral lysosome levels as a critical determinant of mTORC1 inactivation during nutrient stress and may have implications for diseases with aberrant mTORC1 signaling, including cancer.

The online version contains supplementary material available at 10.1186/s12964-026-02659-9.