Department of Food Quality and Safety, School of Public Health, Zunyi Medical University, University West Road No. 6, Xinpu District, Zunyi, 563000, Guizhou, People's Republic of China.
Experimental Teaching Demonstration Center for Preventive Medicine of Guizhou Province, Zunyi, 563000, Guizhou, People's Republic of China.
Arch Toxicol. 2018 Jun;92(6):1913-1923. doi: 10.1007/s00204-018-2210-3. Epub 2018 May 2.
As a vital member of AAA+ (ATPase associated with diverse cellular activities) protein superfamily, Lon, a homo-hexameric ring-shaped protein complex with a serine-lysine catalytic dyad, is highly conserved throughout almost all prokaryotic and eukaryotic organisms. Lon protease (LONP) plays an important role in maintaining mitoproteostasis through selectively recognizing and degrading oxidatively modified mitoproteins within mitochondrial matrix, such as oxidized aconitase, phosphorylated mitochondrial transcription factor A, etc. Furthermore, the up-regulated LONP increased mitochondrial ROS generation to promote cell survival, cell proliferation, epithelial-mesenchymal transition, and cell migration, which was attributed to the up-regulation of NADH:ubiquinone oxidoreductase core subunit S8 via interaction with chaperone Lon under hypoxic or oxidative stress in tumorigenesis. In addition, Lon also participated in protein kinase RNA (PKR)-like endoplasmic reticulum kinase signaling pathway under endoplasmic reticulum (ER) stress. In short, Lon, as a pivotal stress-responsive protein that involved in the crosstalks among mitochondria, ER and nucleus, participated in multifarious important cellular processes crucial for cell survival, such as the mitochondrial protein quality control system, the mitochondrial unfolded protein response, the mtDNA maintenance, and the ER unfolded protein response.
Lon 作为 AAA+（ATPase associated with diverse cellular activities）蛋白超家族的重要成员，是一种同源六聚体环形蛋白复合物，具有丝氨酸-赖氨酸催化二联体，在几乎所有原核和真核生物中都高度保守。Lon 蛋白酶（LONP）通过选择性识别和降解线粒体基质中氧化修饰的线粒体蛋白，如氧化的乌头酸酶、磷酸化的线粒体转录因子 A 等，在维持线粒体蛋白质稳态中发挥重要作用。此外，上调的 LONP 增加了线粒体 ROS 的产生，以促进细胞存活、细胞增殖、上皮-间充质转化和细胞迁移，这归因于在肿瘤发生过程中，Lon 通过与伴侣蛋白 Lon 相互作用，上调 NADH：泛醌氧化还原酶核心亚基 S8，从而增加了 NADH：泛醌氧化还原酶核心亚基 S8 的表达。此外，Lon 还参与了内质网（ER）应激下蛋白激酶 RNA（PKR）样内质网激酶信号通路。总之，Lon 作为一种关键的应激反应蛋白，参与了线粒体、内质网和细胞核之间的串扰，参与了许多对细胞存活至关重要的重要细胞过程，如线粒体蛋白质质量控制系统、线粒体未折叠蛋白反应、mtDNA 维持和内质网未折叠蛋白反应。
