南京大学医学院Zhenji Gan和中国科学院Mengle Shao共同合作，近期取得重要工作进展。他们研究发现 LONP1对线粒体的蛋白水解重组指导脂肪细胞的细胞身份转换。相关研究成果2023年5月22日在线发表于《自然—细胞生物学》杂志上。

据介绍，线粒体蛋白酶是线粒体可塑性的关键调节因子，并通过进行高度调节的蛋白水解反应，作为蛋白质质量监测和调节酶。然而，目前尚不清楚受调节的线粒体蛋白水解是否与细胞身份转换有机制联系。

研究人员报道了冷响应性线粒体蛋白水解是脂肪细胞产热重塑过程中白色至米色脂肪细胞命运编程的先决条件。产热刺激通过线粒体蛋白酶LONP1选择性地促进成熟白色脂肪细胞中的线粒体蛋白稳定。LONP1依赖性蛋白水解的破坏实质上损害了冷或β3肾上腺素能激动剂诱导的成熟脂肪细胞从白色到米色的身份转换。从机制上讲，LONP1选择性降解琥珀酸脱氢酶复合物铁硫亚基B，并确保足够的细胞内琥珀酸水平。这改变了产热基因上的组蛋白甲基化状态，从而实现了脂肪细胞命运编程。最后，LONP1表达的增加提高了琥珀酸水平，并纠正了与衰老相关的白色至米色脂肪细胞转化和脂肪细胞产热能力的损伤。

总之，这些发现揭示了LONP1将蛋白水解监测与线粒体代谢重组联系起来，并在脂肪细胞产热重塑过程中指导细胞身份转换。

附：英文原文

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

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

Issue&Volume: 2023-05-22

Abstract: 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 β3 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.

DOI: 10.1038/s41556-023-01155-3

Source: https://www.nature.com/articles/s41556-023-01155-3