TOR and heat shock response pathways regulate peroxisome biogenesis during proteotoxic stress

Area of Science:

• Cell Biology
• Molecular Biology
• Organelle Dynamics

Background:

• Peroxisomes are vital organelles involved in energy homeostasis and redox balance.
• Peroxisome dysfunction is implicated in various diseases, but their dynamic regulation under cellular stress is not well understood.

Purpose of the Study:

• To investigate the mechanisms controlling peroxisome dynamics during proteotoxic stress.
• To determine the role of peroxisome biogenesis in cellular recovery from proteotoxic stress.

Main Methods:

• Utilized yeast models to study peroxisome responses to various proteotoxic stress conditions.
• Analyzed peroxisome proliferation via de novo biogenesis, growth, and division, contrasting with pexophagy.
• Investigated signaling pathways including heat shock response and Target of Rapamycin (TOR) signaling.
• Validated findings in human fibroblasts.

Main Results:

• Proteotoxic stress, including ER or cytosolic chaperone dysfunction, impaired protein translocation, disrupted glycosylation, or reductive stress, induces peroxisome proliferation.
• Peroxisome proliferation occurs via enhanced de novo biogenesis from the ER, growth, and division, not reduced pexophagy.
• Peroxisome biogenesis is crucial for cellular recovery from proteotoxic stress.
• The response is mediated by heat shock pathway activation and TOR signaling inhibition.
• Similar effects were observed in human cells.

Conclusions:

• Peroxisomes play a critical and conserved role in the cellular response to proteotoxic stress.
• Enhanced peroxisome biogenesis is a key adaptive mechanism for maintaining cellular homeostasis under stress.
• Targeting peroxisome dynamics may offer therapeutic strategies for diseases associated with proteotoxic stress.