华中科技大学Chun Zhang团队近期取得重要工作进展，他们研究提出，MDM2通过HDAC1的泛素化和降解加速肾脏衰老。相关研究成果2024年5月17日在线出版于《中国药理学报》杂志上。

据介绍，衰老是一个复杂而不可避免的生物过程，其特征是体内平衡逐渐丧失和器官功能下降。细胞衰老的病理特征，包括细胞周期停滞、代谢紊乱和衰老相关分泌表型（SASP）的出现，共同促成了衰老的复杂性和多面性。除了与p53的经典相互作用外，小鼠双分钟基因2（MDM2），传统上被称为参与蛋白质降解的E3泛素连接酶，在控制衰老的细胞过程中发挥着关键作用。组蛋白去乙酰化酶（HDAC）是一类主要在细胞核中表达的组蛋白脱酰酶，已成为肾组织衰老的关键因素。

研究人员探讨了MDM2和HDAC1在肾脏衰老中的相互作用。研究人员在小鼠中建立了一个2年的自然衰老模型，该模型通过SA-β-GAL染色和肾脏中衰老相关标志物如p21、p16和TNF-α的表达增加得到了验证。

此外，研究人员发现MDM2的表达显著增加，而HDAC1的表达在肾脏衰老过程中下调。在体外H₂O₂刺激的HK2细胞中证实了这一现象。敲除肾小管MDM2减轻了衰老小鼠的肾脏衰老和H₂O₂刺激的HK2细胞的衰老。

此外，研究人员证明MDM2通过协调HDAC1的泛素化和随后的降解来促进肾脏衰老。这些机制协同加速了肾组织的衰老过程，突出了MDM2和HDAC1之间复杂的相互作用，支持了与年龄相关的器官功能下降。

附：英文原文

Title: MDM2 accelerated renal senescence via ubiquitination and degradation of HDAC1

Author: Xiang, Hui-ling, Yuan, Qian, Zeng, Jie-yu, Xu, Zi-yu, Zhang, Hui-zi, Huang, Jing, Song, An-ni, Xiong, Jing, Zhang, Chun

Issue&Volume: 2024-05-17

Abstract: Senescence, an intricate and inevitable biological process, characterized by the gradual loss of homeostasis and declining organ functions. The pathological features of cellular senescence, including cell cycle arrest, metabolic disruptions, and the emergence of senescence-associated secretory phenotypes (SASP), collectively contribute to the intricate and multifaceted nature of senescence. Beyond its classical interaction with p53, murine double minute gene 2 (MDM2), traditionally known as an E3 ubiquitin ligase involved in protein degradation, plays a pivotal role in cellular processes governing senescence. Histone deacetylase (HDAC), a class of histone deacetylases mainly expressed in the nucleus, has emerged as a critical contributor to renal tissues senescence. In this study we investigated the interplay between MDM2 and HDAC1 in renal senescence. We established a natural aging model in mice over a 2-year period that was verified by SA-β-GAL staining and increased expression of senescence-associated markers such as p21, p16, and TNF-α in the kidneys. Furthermore, we showed that the expression of MDM2 was markedly increased, while HDAC1 expression underwent downregulation during renal senescence. This phenomenon was confirmed in H2O2-stimulated HK2 cells in vitro. Knockout of renal tubular MDM2 alleviated renal senescence in aged mice and in H2O2-stimulated HK2 cells. Moreover, we demonstrated that MDM2 promoted renal senescence by orchestrating the ubiquitination and subsequent degradation of HDAC1. These mechanisms synergistically accelerate the aging process in renal tissues, highlighting the intricate interplay between MDM2 and HDAC1, underpinning the age-related organ function decline.

DOI: 10.1038/s41401-024-01294-9

Source: https://www.nature.com/articles/s41401-024-01294-9