Proteolytic rewiring of mitochondria by LONP1 directs cell identity switching of adipocytes

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作   者：

Chen, Xinyi;  Yin, Yujing;  Zhou, Danxia;  Xu, Zhisheng;  Liu, Lin;  Xiao, Liwei;  Mao, Yan;  Yang, Likun;  Zhang, Xue-Na;  Wan, Qiangyou;  Lu, Bin;  Chen, Yuncong;  Zhu, Min-Sheng;  Scherer, Philipp E.;  Fang, Lei;  Piao, Hai-Long;  Shao, Mengle;  Gan, Zhenji;  Fu, Tingting;  Sun, Wanping;  Xue, Jiachen;  Zhou, Zheng;  Wang, Wen;  Guo, Qiqi; 

作者机构：

Touchstone Diabet Ctr;  Chinese Acad Sci;  Nanjing Univ;  Univ South China;  Chinese Academy of Sciences;  Hengyang Med Coll;  Univ Texas Southwestern Med Ctr;  Ctr Microbes Dev & Hlth;  Chem & Biomed Innovat Ctr ChemBIC;  Nanjing University; 

关键词：

THERMOGENESIS;  COMPLEX;  PROTEIN;  DISEASE;  SUCCINATE;  MUTATIONS;  AUTOPHAGY;  TRACKING ADIPOGENESIS;  BROWN;  PROTEASES; 

期刊名称：

Nature cell biology

i s s n：

1465-7392

年卷期：

2023 年 25 卷 6 期

页   码：

848-864

页   码：

摘   要：

Fu, Sun, Xue, Zhou et al. show that the mitoprotease LONP1 selectively degrades a complex II component to control intracellular succinate levels, which is needed for white-to-beige adipocyte cell fate programming during adipocyte thermogenic remodelling. Mitochondrial proteases are emerging as key regulators of mitochondrial plasticity and acting as both protein quality surveillance and regulatory enzymes by performing highly regulated proteolytic reactions. However, it remains unclear whether the regulated mitochondrial proteolysis is mechanistically linked to cell identity switching. Here we report that cold-responsive mitochondrial proteolysis is a prerequisite for white-to-beige adipocyte cell fate programming during adipocyte thermogenic remodelling. Thermogenic stimulation selectively promotes mitochondrial proteostasis in mature white adipocytes via the mitochondrial protease LONP1. Disruption of LONP1-dependent proteolysis substantially impairs cold- or beta(3) adrenergic agonist-induced white-to-beige identity switching of mature adipocytes. Mechanistically, LONP1 selectively degrades succinate dehydrogenase complex iron sulfur subunit B and ensures adequate intracellular succinate levels. This alters the histone methylation status on thermogenic genes and thereby enables adipocyte cell fate programming. Finally, augmented LONP1 expression raises succinate levels and corrects ageing-related impairments in white-to-beige adipocyte conversion and adipocyte thermogenic capacity. Together, these findings reveal that LONP1 links proteolytic surveillance to mitochondrial metabolic rewiring and directs cell identity conversion during adipocyte thermogenic remodelling.