Related Experiment Video
Updated: Jan 22, 2026
Exploring the Regulation of Lipid Droplet Catabolism through Lipophagy
Published on: January 31, 2025
Peripheral lysosome levels dictate mTORC1 inactivation even when catabolically impaired
Huy Quang Dang1, Therése Forssén1, Spyridon Pantelios1
1Department of Laboratory Medicine, Division of Pathology, Karolinska Institutet, Stockholm, Sweden.
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.
Insights
Lysosome positioning controls mTORC1 activity during nutrient starvation. Moving lysosomes away from the cell center is crucial for suppressing mechanistic target of rapamycin complex 1 (mTORC1) signaling when nutrients are scarce.
Area of Science:
- Cell Biology
- Molecular Biology
- Cancer Biology
Background:
- Mechanistic target of rapamycin complex 1 (mTORC1) drives cell growth and is often hyperactivated in cancer.
- mTORC1 activation occurs at the lysosome in response to nutrients, but its inactivation mechanisms are unclear.
Purpose of the Study:
- To investigate the mechanisms regulating mechanistic target of rapamycin complex 1 (mTORC1) inactivation during nutrient starvation.
- To determine the role of lysosome positioning in mTORC1 signaling dynamics.
Main Methods:
- Utilized cell culture models under conditions of leucine or arginine starvation.
- Investigated lysosome translocation using microscopy and biochemical assays.
- Assessed mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway activity.
- Manipulated lysosome positioning and monitored mTORC1 activity.
Main Results:
- Sustained mechanistic target of rapamycin complex 1 (mTORC1) suppression requires peripheral lysosome translocation to the perinuclear region during starvation.
- Active mechanistic target of rapamycin (mTOR) at peripheral lysosomes can sustain mTORC1 activity.
- Preventing lysosome translocation maintains mTORC1 signaling by modulating PI3K/Akt signaling, independent of autophagy.
Conclusions:
- Peripheral lysosome localization is critical for mechanistic target of rapamycin complex 1 (mTORC1) inactivation during nutrient stress.
- Lysosome positioning influences PI3K/Akt signaling, thereby regulating mTORC1 activity.
- Aberrant mTORC1 signaling in diseases like cancer may be linked to dysregulated lysosome positioning.
Related Concept Videos
01:58X-Inactivation
01:30Carbohydrate Catabolism
01:25Lipid Catabolism
01:31Lysosomes
01:18Amino Acid Catabolism
01:22Lysosomal Hydrolases