MCU-dependent mitochondrial Ca2+ inhibits NAD+/SIRT3/SOD2 pathway to promote ROS production and metastasis of HCC cells
MCU-dependent mitochondrial Ca2+ inhibits NAD+/SIRT3/SOD2 pathway to promote ROS production and metastasis of HCC cells
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DOI：
10.1038/onc.2017.167
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发表时间：
2017-10-19
期刊：
影响因子：
8
通讯作者：
Xing, J.
中科院分区：
文献类型：
--
作者：
Ren, T.;Zhang, H.;Xing, J.
线粒体Ca 2+信号转导是一种依赖于线粒体Ca 2+单向转运体（MCU）的信号转导途径，在能量代谢、活性氧（ROS）产生和细胞凋亡等生理病理过程中发挥着重要作用。然而，线粒体Ca 2+信号是如何重塑的机制的理解及其功能的作用仍然非常有限的癌症，特别是在肝细胞癌。在这里，我们证明了MCU复合物在肝细胞癌（HCC）细胞中表达异常，并与HCC患者的转移和预后不良显著相关。MCU的上调明显增强了线粒体对Ca 2+的摄取，并通过下调NAD（+）/还原型烟酰胺腺嘌呤二核苷酸（NADH）的比值和沉默调节蛋白3的NAD+依赖性脱乙酰酶活性来抑制超氧化物歧化酶2（SOD 2）活性，从而显著促进ROS的产生。此外，我们的数据表明，MCU依赖的线粒体Ca 2+摄取通过ROS激活的c-Jun N-末端激酶途径促进基质金属蛋白酶-2活性和细胞运动，从而有助于增加HCC细胞的体外侵袭和迁移能力以及体内肝内和远端肺转移能力。此外，线粒体钙缓冲蛋白parvalbumin治疗显着抑制ROS的产生和HCC转移的能力。我们的研究揭示了线粒体Ca 2+稳态重塑与ROS产生之间的联系机制，并为HCC中MCU依赖的线粒体Ca 2+摄取的转移促进作用提供了证据。我们的研究结果表明，线粒体钙摄取机制可能是一个新的治疗肝癌转移的目标。
Mitochondrial Ca2+ signaling, which is strongly dependent on the mitochondrial Ca2+ uniporter (MCU) complex, has a series of key roles in physiopathological processes, including energy metabolism, reactive oxygen species (ROS) production and cell apoptosis. However, a mechanistic understanding of how the mitochondrial Ca2+ signaling is remodeled and its functional roles remains greatly limited in cancers, especially in hepatocellular carcinoma. Here we demonstrated that the MCU complex was dysregulated in hepatocellular carcinoma (HCC) cells and significantly correlated with metastasis and poor prognosis of HCC patients. Upregulation of MCU clearly enhanced the Ca2+ uptake into mitochondria, which significantly promoted ROS production by downregulating nicotinamide adenine dinucleotide(+) (NAD(+))/reduced form of nicotinamide adenine dinucleotid (NADH) ratio and the NAD+-dependent deacetylase activity of sirtuin 3 to inhibit superoxide dismutase 2 (SOD2) activity. Moreover, our data indicated that the MCU-dependent mitochondrial Ca2+ uptake promotes matrix metalloproteinase-2 activity and cell motility by ROS-activated c-Jun N-terminal kinase pathway, and thus contributed to the increased ability of invasion and migration in vitro and intrahepatic and distal lung metastasis in vivo of HCC cells. In addition, treatment with the mitochondrial Ca2+-buffering protein parvalbumin significantly suppressed ROS production and the ability of HCC metastasis. Our study uncovers a mechanism that links the remodeling of mitochondrial Ca2+ homeostasis to ROS production, and provides evidence supporting a metastasis-promoting role for the MCU-dependent mitochondrial Ca2+ uptake in HCC. Our findings suggest that the mitochondrial Ca2+ uptake machinery may potentially be a novel therapeutic target for HCC metastasis.