Zhao Wen-Hao, Huang Hua, Ding Chen, Zhao Ze-Xia, Jia Chao-Yi, Wang Ying-Jie, Hu Zi-Xuan, Wang Guan-Nan, Li Yong-Wen, Liu Jing-Hao, Liu Hong-Yu, Chen Jun
Department of Lung Cancer Surgery, Tianjin Medical University General Hospital, Tianjin, 300052, China.
Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, 300052, China.
Acta Pharmacol Sin. 2025 Aug 6. doi: 10.1038/s41401-025-01625-4.
Hypoxia is a common phenomenon in the microenvironment of solid tumors; mitochondria, as the site of cellular oxidative respiration, are among the first organelles to be affected under hypoxic conditions. Mitochondrial cristae organizing protein 19 (MIC19), a core component of the mitochondrial contact site and cristae organizing system (MICOS), is essential for preserving mitochondrial activity. In this study, we investigated the effects of hypoxia on MIC19 and its regulatory mechanisms in non-small cell lung cancer (NSCLC). We showed that the expression levels of MIC19 were significantly increased in NSCLC, which were associated with advanced stages and a poor prognosis in patients with NSCLC. We demonstrated that MIC19 promoted the proliferation and invasion of A549 and PC9 cells in vitro, and MIC19 played a crucial role in maintaining mitochondrial function. We revealed that USP3 mediated the hypoxia-induced upregulation of MIC19 expression in A549 and PC9 cells. In the hypoxic microenvironment, HIF-1α bound to the USP3 promoter region and promoted USP3 expression, which in turn stabilized MIC19 through K48-linked deubiquitination, thereby driving NSCLC progression. The role of MIC19 in NSCLC growth and progression was confirmed in nude mice bearing A549 xenograft tumors in vivo. In conclusion, under hypoxic conditions, USP3 stabilizes MIC19 through deubiquitination, thereby promoting NSCLC progression. This study reveals the HIF1α-USP3-MIC19 axis in NSCLC progression, providing a theoretical basis for future therapeutic strategies.
缺氧是实体瘤微环境中的常见现象；线粒体作为细胞氧化呼吸的场所，是在缺氧条件下最早受到影响的细胞器之一。线粒体嵴组织蛋白19（MIC19）是线粒体接触位点和嵴组织系统（MICOS）的核心成分，对维持线粒体活性至关重要。在本研究中，我们调查了缺氧对非小细胞肺癌（NSCLC）中MIC19的影响及其调控机制。我们发现，NSCLC中MIC19的表达水平显著升高，这与NSCLC患者的晚期阶段和不良预后相关。我们证明，MIC19在体外促进A549和PC9细胞的增殖和侵袭，并且MIC19在维持线粒体功能中起关键作用。我们揭示，USP3介导缺氧诱导的A549和PC9细胞中MIC19表达上调。在缺氧微环境中，HIF-1α与USP3启动子区域结合并促进USP3表达，进而通过K48连接的去泛素化使MIC19稳定，从而推动NSCLC进展。在体内携带A549异种移植肿瘤的裸鼠中证实了MIC19在NSCLC生长和进展中的作用。总之，在缺氧条件下，USP3通过去泛素化使MIC19稳定，从而促进NSCLC进展。本研究揭示了NSCLC进展中的HIF1α-USP3-MIC19轴，为未来的治疗策略提供了理论基础。
