Related Experiment Video

Updated: May 17, 2025

Using Caenorhabditis elegans to Screen for Tissue-Specific Chaperone Interactions
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Using Caenorhabditis elegans to Screen for Tissue-Specific Chaperone Interactions

Published on: June 7, 2020

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Chaperone-mediated autophagy manipulates PGC1α stability and governs energy metabolism under thermal stress

Yixiao Zhuang1, Xinyi Zhang1, Shuang Zhang1

  • 1State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, 200438, China.

Nature Communications
|May 13, 2025
PubMed

Insights

Chaperone-mediated autophagy (CMA) regulates thermogenic protein PGC1α stability during thermal stress. PARK7 protein controls CMA activity, impacting brown adipose tissue (BAT) function and metabolic health.

Area of Science:

  • Cellular Biology
  • Metabolism
  • Protein Degradation

Background:

  • Thermogenic proteins like PGC1α are crucial for energy expenditure but are down-regulated under thermal stress.
  • The precise molecular mechanisms controlling PGC1α stability during thermal stress are not fully understood.
  • Chaperone-mediated autophagy (CMA) is a potential regulator of protein stability.

Purpose of the Study:

  • To investigate the role of CMA in regulating PGC1α stability under thermal stress.
  • To identify the molecular players involved in CMA-mediated regulation of PGC1α in brown adipose tissue (BAT).

Main Methods:

  • Utilized mouse models with knockdown of Lamp2a (a CMA component) in BAT.
  • Employed proteomics of BAT, structure prediction, co-immunoprecipitation-mass spectrometry, and biochemical assays.
  • Investigated the function of PARK7 in regulating CMA activity and its impact on BAT metabolism.

Main Results:

  • Knockdown of Lamp2a in BAT increased PGC1α protein levels and improved metabolic phenotypes.
  • PARK7 was identified as a temperature sensor that interacts with LAMP2A and HSC70 to modulate CMA activity.
  • Park7 knockout in BAT led to BAT whitening, impaired insulin sensitivity, and reduced energy expenditure at thermoneutrality.
  • Inhibiting CMA by LAMP2A knockdown reversed the effects of Park7 ablation.

Conclusions:

  • CMA is essential for maintaining brown adipose tissue function during thermoneutrality by degrading PGC1α.
  • PARK7 plays a critical role in sensing temperature and regulating CMA activity, thereby influencing BAT thermogenesis and metabolic health.

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