Chaperone-mediated autophagy manipulates PGC1α stability and governs energy metabolism under thermal stress
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 th...
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Nature Portfolio
2025-05-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-59618-0 |
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| author | 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 Xingxing Kong |
| author_facet | 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 Xingxing Kong |
| author_sort | Yixiao Zhuang |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-3a1d176064e241ce985d3bc2eb34b1ee |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Portfolio |
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| series | Nature Communications |
| spelling | doaj-art-3a1d176064e241ce985d3bc2eb34b1ee2025-08-20T01:51:36ZengNature PortfolioNature Communications2041-17232025-05-0116111610.1038/s41467-025-59618-0Chaperone-mediated autophagy manipulates PGC1α stability and governs energy metabolism under thermal stressYixiao Zhuang0Xinyi Zhang1Shuang Zhang2Yunpeng Sun3Hui Wang4Yuxuan Chen5Hanyin Zhang6Penglai Zou7Yonghao Feng8Xiaodan Lu9Peijie Chen10Yi Xu11John Zhong Li12Huanqing Gao13Li Jin14Xingxing Kong15State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan UniversityState Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan UniversityState Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan UniversityInterdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of SciencesState Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan UniversityState Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan UniversityState Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan UniversityState Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan UniversityState Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan UniversityPrecisional Medical Center, Jilin Province People’s HospitalSchool of Exercise and Health, Shanghai University of SportShanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Fudan UniversityDepartment of Molecular Biology and Biochemistry, Nanjing Medical UniversityState Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan UniversityState Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan UniversityState Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan UniversityAbstract 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.https://doi.org/10.1038/s41467-025-59618-0 |
| spellingShingle | 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 Xingxing Kong Chaperone-mediated autophagy manipulates PGC1α stability and governs energy metabolism under thermal stress Nature Communications |
| title | Chaperone-mediated autophagy manipulates PGC1α stability and governs energy metabolism under thermal stress |
| title_full | Chaperone-mediated autophagy manipulates PGC1α stability and governs energy metabolism under thermal stress |
| title_fullStr | Chaperone-mediated autophagy manipulates PGC1α stability and governs energy metabolism under thermal stress |
| title_full_unstemmed | Chaperone-mediated autophagy manipulates PGC1α stability and governs energy metabolism under thermal stress |
| title_short | Chaperone-mediated autophagy manipulates PGC1α stability and governs energy metabolism under thermal stress |
| title_sort | chaperone mediated autophagy manipulates pgc1α stability and governs energy metabolism under thermal stress |
| url | https://doi.org/10.1038/s41467-025-59618-0 |
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