线粒体 Lon 蛋白酶参与线粒体铁代谢并介导 p53 降解调控肿瘤细胞 Ferroptosis 的机制研究

Lon protease plays an important role in the quality control of mitochondrial proteins and regulation of mitochondrial protein homeostasis, which ensures the cellular metabolism in well organized. In our previous study, we found that Lon protease is highly expressed in a variety of tumor cells and tissues, and was closely related to the tumorigenesis and tumor drug resistance. In addition, p53 protein level is dramatically increased in non-small cell lung cancer (NSCLC) cells with low expression of Lon, and its molecular mechanism remains to be elucidated. Moreover, Lon plays crucial roles in regulating homeostasis of iron metabolism related proteins, such as ALAS-1, heme, Fe-S clusters and ISCU. In different physiological and pathological conditions, Lon affects cellular energy metabolism and cell death including Ferroptosis by regulating those proteins. This project will investigate Lon mediated p53 degradation and iron proteins homeostasis to reveal the molecular mechanism of Lon protease in the regulation of Ferroptosis, a nonapoptotic cell death, as well as the effects on tumor cells proliferation, invasion and metastasis. The results will be of important theoretical significance and potential application value in further understanding the molecular mechanism of Ferroptosis, which may also provide us a novel target for early diagnosis and treatment of cancers, as well as a prognostic markers and searching for new target for drug resistant.

Lon蛋白酶在线粒体蛋白质量控制机器中起着重要作用，它通过调控线粒体蛋白的稳态平衡，确保细胞代谢正常。我们前期研究发现，Lon在多种肿瘤细胞及肿瘤组织中高表达，与肿瘤发生发展及耐药性密切相关；p53蛋白在Lon下调的非小细胞肺癌细胞中显著增加，但机制尚不清楚。此外，Lon对线粒体铁代谢相关蛋白ALAS-1，Heme，Fe-S簇和ISCU在细胞内的稳态平衡中也起着重要的调节作用。不同生理和病理状态下，Lon通过调控这些蛋白影响细胞能量代谢及包括铁死亡在内的细胞死亡。本项目将研究Lon介导p53降解以及相关的含铁蛋白的体内稳态平衡，揭示Lon蛋白酶在“铁死亡”这一非凋亡细胞死亡过程中的作用，以及影响肿瘤细胞的增殖、侵袭和转移的分子机制，对进一步理解铁死亡分子机制的内涵具有重要的理论意义和潜在的临床应用价值，为早期诊断和治疗肿瘤、改善肿瘤患者预后及抗耐药肿瘤新药提供新的靶点。