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

Author

Listed:
  • Yixiao Zhuang

    (Fudan University)

  • Xinyi Zhang

    (Fudan University)

  • Shuang Zhang

    (Fudan University)

  • Yunpeng Sun

    (Chinese Academy of Sciences)

  • Hui Wang

    (Fudan University)

  • Yuxuan Chen

    (Fudan University)

  • Hanyin Zhang

    (Fudan University)

  • Penglai Zou

    (Fudan University)

  • Yonghao Feng

    (Fudan University)

  • Xiaodan Lu

    (Jilin Province People’s Hospital)

  • Peijie Chen

    (Shanghai University of Sport)

  • Yi Xu

    (Fudan University)

  • John Zhong Li

    (Nanjing Medical University
    Nanjing Medical University
    Nanjing Medical University)

  • Huanqing Gao

    (Fudan University)

  • Li Jin

    (Fudan University)

  • Xingxing Kong

    (Fudan University
    Fudan University
    Fudan University)

Abstract

Thermogenic proteins are down-regulated under thermal stress, including PGC1α· However, the molecular mechanisms are not fully understood. Here, we addressed that chaperone-mediated autophagy could regulate the stability of PGC1α under thermal stress. In mice, knockdown of Lamp2a, one of the two components of CMA, in BAT showed increased PGC1α protein and improved metabolic phenotypes. Combining the proteomics of brown adipose tissue (BAT), structure prediction, co-immunoprecipitation- mass spectrum and biochemical assays, we found that PARK7, a Parkinson’s disease causative protein, could sense the temperature changes and interact with LAMP2A and HSC70, respectively, subsequently manipulate the activity of CMA. Knockout of Park7 specific in BAT promoted BAT whitening, leading to impaired insulin sensitivity and energy expenditure at thermoneutrality. Moreover, inhibiting the activity of CMA by knockdown of LAMP2A reversed the effects induced by Park7 ablation. These findings suggest CMA is required for BAT to sustain thermoneutrality-induced whitening through degradation of PGC1α.

Suggested Citation

  • Yixiao Zhuang & Xinyi Zhang & Shuang Zhang & Yunpeng Sun & Hui Wang & Yuxuan Chen & Hanyin Zhang & Penglai Zou & Yonghao Feng & Xiaodan Lu & Peijie Chen & Yi Xu & John Zhong Li & Huanqing Gao & Li Jin, 2025. "Chaperone-mediated autophagy manipulates PGC1α stability and governs energy metabolism under thermal stress," Nature Communications, Nature, vol. 16(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-59618-0
    DOI: 10.1038/s41467-025-59618-0
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    References listed on IDEAS

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    1. Akiko Kuma & Masahiko Hatano & Makoto Matsui & Akitsugu Yamamoto & Haruaki Nakaya & Tamotsu Yoshimori & Yoshinori Ohsumi & Takeshi Tokuhisa & Noboru Mizushima, 2004. "The role of autophagy during the early neonatal starvation period," Nature, Nature, vol. 432(7020), pages 1032-1036, December.
    2. Huanqing Gao & Liang Zhou & Yiming Zhong & Zhen Ding & Sixiong Lin & Xiaoting Hou & Xiaoqian Zhou & Jie Shao & Fan Yang & Xuenong Zou & Huiling Cao & Guozhi Xiao, 2022. "Kindlin-2 haploinsufficiency protects against fatty liver by targeting Foxo1 in mice," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
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