马兜铃酸 I 诱导线粒体 Ca2 积累，触发 MitoROS 的产生并激活肝细胞癌细胞中的 Src/FAK 通路。
Aristolochic acid I induced mitochondrial Ca2+ accumulation triggers the production of MitoROS and activates Src/FAK pathway in hepatocellular carcinoma cells.
发表日期：2024 Oct 17
作者：
Yongkang Hu, Qi Zhang, Wenjuan Jiang, Xian Wang, Xinlong Guo, Langqun Chen, Siyu Cheng, Jiahui Ying, Jing Ye, Zhang Liang
来源：
CHEMICO-BIOLOGICAL INTERACTIONS
摘要：
马兜铃酸 I (AAI) 是马兜铃酸 (AA) 中的肾毒性和致癌化合物之一。最近的研究报告了其对肝细胞癌的促进作用。然而，AAI导致HCC发生的潜在机制仍不清楚。在这里，我们发现 AAI 暴露引起线粒体功能的改变，其特点是 Hepa1-6 和 HepG2 细胞中 ATP 水平和线粒体膜电位增加，线粒体 Ca2 和线粒体 ROS (MitoROS) 积累。线粒体 Ca2 摄取的限制减轻了这些影响。我们的结果表明，MitoROS 的增加与 AAI 诱导的 HCC 细胞迁移和侵袭有关。 MitoROS/Src/FAK通路参与AAI诱导的HCC细胞的迁移和侵袭。总之，我们的研究表明AAI通过促进线粒体Ca2+的积累来影响HCC细胞的线粒体代谢。这些效应导致 AAI 处理的 HCC 细胞中 MitoROS/SRC/FAK 通路的激活，进而诱导细胞迁移和侵袭。版权所有 © 2024。由 Elsevier B.V. 出版。
Aristolochic acid I (AAI) is one of the nephrotoxic and carcinogenic compounds in Aristolochic acids (AAs). Recent studies have reported its promoting effect on hepatocellular carcinoma. However, the underlying mechanisms of AAI for the development of HCC is still unclear. Here, we found that AAI exposure caused alterations in mitochondrial function, which featured with increased ATP level and mitochondrial membrane potential, accumulation of mitochondrial Ca2+ and mitochondrial ROS (MitoROS) in Hepa1-6 and HepG2 cells. The restriction of mitochondrial Ca2+ uptake alleviated these effects. Our results showed that increased MitoROS was associated with AAI-induced migration and invasion in HCC cells. MitoROS/Src/FAK pathway was involved in the AAI-induced migration and invasion of HCC cells. In summary, our study showed that AAI affected mitochondrial metabolism of HCC cells by promoting the accumulation of mitochondrial Ca2+. These effects resulted in the activation of the MitoROS/SRC/FAK pathway in AAI-treated HCC cells, which in turn induced cell migration and invasion.Copyright © 2024. Published by Elsevier B.V.