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Updated: Jun 3, 2025

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mTOR signaling controls protein aggregation during heat stress and cellular aging in a translation- and

Arthur Fischbach1, Per O Widlund1, Xinxin Hao1

  • 1Institute for Biomedicine, Sahlgrenska Academy, Centre for Ageing and Health-AgeCap, University of Gothenburg, Gothenburg, Sweden.

The Journal of Biological Chemistry
|January 11, 2025
PubMed

Insights

The mechanistic target of rapamycin (mTOR) pathway drives protein aggregation during aging and heat stress. Inhibiting mTOR prevents aggregation without affecting translation, revealing a new role for this pathway.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Aging Research

Background:

  • The mechanistic target of rapamycin (mTOR) pathway regulates protein synthesis and is implicated in aging.
  • The role of mTOR in protein misfolding and aggregation, particularly during stress and aging, is not well understood.

Purpose of the Study:

  • To investigate the role of the mTOR signaling pathway in protein aggregation during heat stress and cellular aging.
  • To identify key regulators within the mTOR pathway and associated complexes involved in protein aggregation.

Main Methods:

  • Utilized Saccharomyces cerevisiae as a model organism.
  • Performed a synthetic genetic array screen to identify genetic interactions.
  • Manipulated mTOR activity by deleting key subunits (TCO89 for mTORC1, NPR3 for Seh1-associated complex).
  • Assessed protein aggregation levels under heat stress and aging conditions.

Main Results:

  • Reduced mTOR activity via TCO89 deletion significantly prevented protein aggregation during heat stress and aging.
  • This protective effect occurred independently of global translation rates and Hsf1-dependent stress response.
  • Increased mTOR activity via NPR3 deletion exacerbated protein aggregation without overactivating translation.

Conclusions:

  • The mTOR signaling pathway is a critical regulator of protein aggregation during cellular aging and heat shock.
  • mTOR's influence on protein aggregation is separable from its effects on global translation rates and the Hsf1 stress response.
  • Targeting the mTOR pathway offers a potential strategy to mitigate age-associated and stress-induced protein aggregation.
Keywords:
GATORagingmTORprotein aggregationproteinopathyproteostasisspatial protein quality control

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