广州医科大学冯杜团队发现，TFAM是一种自噬受体，它通过与细胞质线粒体DNA结合来限制炎症的发生。2024年5月23日，国际知名学术期刊《自然—细胞生物学》在线发表了这一成果。

研究人员发现，线粒体转录因子A（TFAM），一种与线粒体DNA（mtDNA）结合的蛋白质，通过自噬溶酶体途径与自噬蛋白LC3相互作用（被称之为拟核自噬），有助于消除泄漏的mtDNA。TFAM含有一个被称为LC3相互作用区（LIR）的分子代码，可实现这种结合。

虽然突变TFAM的LIR motif不会影响其正常的线粒体功能，但细胞胞质中积累了更多的mtDNA，激活了炎症信号通路。因此，TFAM介导自噬清除泄漏的mtDNA，从而限制炎症。确定这一机制有助于进一步了解细胞如何利用自噬机制选择性地靶向和降解炎性mtDNA。这些发现可为涉及线粒体损伤和炎症的疾病研究提供参考。

据介绍，当细胞受到压力时，产生能量的线粒体中的 DNA 如果不被清除，就会泄漏出来，引发炎症免疫反应。细胞采用一种名为自噬的质量控制系统来专门降解受损成分。

附：英文原文

Title: TFAM is an autophagy receptor that limits inflammation by binding to cytoplasmic mitochondrial DNA

Author: Liu, Hao, Zhen, Cien, Xie, Jianming, Luo, Zhenhuan, Zeng, Lin, Zhao, Guojun, Lu, Shaohua, Zhuang, Haixia, Fan, Hualin, Li, Xia, Liu, Zhaojie, Lin, Shiyin, Jiang, Huilin, Chen, Yuqian, Cheng, Jiahao, Cao, Zhiyu, Dai, Keyu, Shi, Jinhua, Wang, Zhaohua, Hu, Yongquan, Meng, Tian, Zhou, Chuchu, Han, Zhiyuan, Huang, Huansen, Zhou, Qinghua, He, Pengcheng, Feng, Du

Issue&Volume: 2024-05-23

Abstract: When cells are stressed, DNA from energy-producing mitochondria can leak out and drive inflammatory immune responses if not cleared. Cells employ a quality control system called autophagy to specifically degrade damaged components. We discovered that mitochondrial transcription factor A (TFAM)—a protein that binds mitochondrial DNA (mtDNA)—helps to eliminate leaked mtDNA by interacting with the autophagy protein LC3 through an autolysosomal pathway (we term this nucleoid-phagy). TFAM contains a molecular zip code called the LC3 interacting region (LIR) motif that enables this binding. Although mutating TFAM’s LIR motif did not affect its normal mitochondrial functions, more mtDNA accumulated in the cell cytoplasm, activating inflammatory signalling pathways. Thus, TFAM mediates autophagic removal of leaked mtDNA to restrict inflammation. Identifying this mechanism advances understanding of how cells exploit autophagy machinery to selectively target and degrade inflammatory mtDNA. These findings could inform research on diseases involving mitochondrial damage and inflammation.

DOI: 10.1038/s41556-024-01419-6

Source: https://www.nature.com/articles/s41556-024-01419-6