Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
Cell Death Dis. 2024 Feb 20;15(2):155. doi: 10.1038/s41419-024-06536-6.
Mitochondrial transfer plays an important role in various diseases, and many mitochondrial biological functions can be regulated by HMGB1. To explore the role of mitochondrial transfer in hepatocellular carcinoma (HCC) and its relationship with HMGB1, field emission scanning electron microscopy, immunofluorescence, and flow cytometry were used to detect the mitochondrial transfer between HCC cells. We found that mitochondrial transfer between HCC cells was confirmed using tunnel nanotubes (TNTs). The transfer of mitochondria from the highly invasive HCC cells to the less invasive HCC cells could enhance the migration and invasion ability of the latter. The hypoxic conditions increased the mitochondrial transfer between HCC cells. Then the mechanism was identified using co-immunoprecipitation, luciferase reporter assay, and chromatin immunoprecipitation. We found that RHOT1, a mitochondrial transport protein, promoted mitochondrial transfer and the migration and metastasis of HCC cells during this process. Under hypoxia, HMGB1 further regulated RHOT1 expression by increasing the expression of NFYA and NFYC subunits of the NF-Y complex. RAC1, a protein associated with TNTs formation, promoted mitochondrial transfer and HCC development. Besides, HMGB1 regulated RAC1 aggregation to the cell membrane under hypoxia. Finally, the changes and significance of related molecules in clinical samples of HCC were analyzed using bioinformatics and tissue microarray analyses. We found that HCC patients with high HMGB1, RHOT1, or RAC1 expression exhibited a relatively shorter overall survival period. In conclusion, under hypoxic conditions, HMGB1 promoted mitochondrial transfer and migration and invasion of HCC cells by increasing the expression of mitochondrial transport protein RHOT1 and TNTs formation-related protein RAC1.
线粒体转移在各种疾病中发挥着重要作用，许多线粒体生物学功能可以通过 HMGB1 进行调节。为了探讨线粒体转移在肝细胞癌（HCC）中的作用及其与 HMGB1 的关系，我们使用场发射扫描电子显微镜、免疫荧光和流式细胞术检测了 HCC 细胞之间的线粒体转移。我们发现 HCC 细胞之间的线粒体转移是通过隧道纳米管（TNTs）来确认的。来自高侵袭性 HCC 细胞的线粒体转移到侵袭性较低的 HCC 细胞中，可以增强后者的迁移和侵袭能力。缺氧条件增加了 HCC 细胞之间的线粒体转移。然后通过共免疫沉淀、荧光素酶报告基因测定和染色质免疫沉淀来确定机制。我们发现，线粒体转运蛋白 RHOT1 在这个过程中促进了线粒体转移以及 HCC 细胞的迁移和转移。在缺氧条件下，HMGB1 通过增加 NF-Y 复合物的 NFYA 和 NFYC 亚基的表达进一步调节 RHOT1 的表达。与 TNTs 形成相关的 RAC1 蛋白促进了线粒体转移和 HCC 的发展。此外，HMGB1 在缺氧条件下调节 RAC1 聚集到细胞膜。最后，使用生物信息学和组织微阵列分析分析了 HCC 临床样本中相关分子的变化和意义。我们发现，HMGB1、RHOT1 或 RAC1 表达较高的 HCC 患者的总生存期相对较短。总之，在缺氧条件下，HMGB1 通过增加线粒体转运蛋白 RHOT1 的表达和 TNTs 形成相关蛋白 RAC1 的聚集来促进线粒体转移以及 HCC 细胞的迁移和侵袭。
