State Key Laboratory of Cancer Biology and Experimental Teaching Center of Basic Medicine, Fourth Military Medical University, Xi'an, China.
Department of Pain Treatment, Tangdu Hospital, Fourth Military Medical University, Xi'an, China.
Oncogene. 2017 Oct 19;36(42):5897-5909. doi: 10.1038/onc.2017.167. Epub 2017 Jun 26.
Mitochondrial Ca signaling, which is strongly dependent on the mitochondrial Ca 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 Ca 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 Ca 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 Ca 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 Ca-buffering protein parvalbumin significantly suppressed ROS production and the ability of HCC metastasis. Our study uncovers a mechanism that links the remodeling of mitochondrial Ca homeostasis to ROS production, and provides evidence supporting a metastasis-promoting role for the MCU-dependent mitochondrial Ca uptake in HCC. Our findings suggest that the mitochondrial Ca uptake machinery may potentially be a novel therapeutic target for HCC metastasis.
线粒体钙信号转导强烈依赖于线粒体钙单向转运体（MCU）复合物，在生理病理过程中具有一系列关键作用，包括能量代谢、活性氧（ROS）产生和细胞凋亡。然而，对于线粒体钙信号如何重塑及其在癌症中的功能作用的机制理解仍然非常有限，特别是在肝细胞癌中。在这里，我们证明 MCU 复合物在肝细胞癌（HCC）细胞中失调，并且与 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的钙摄取，这通过下调烟酰胺腺嘌呤二核苷酸（NAD）/还原型烟酰胺腺嘌呤二核苷酸（NADH）比值和 NAD 依赖性去乙酰化酶活性来显著促进 ROS 产生，从而抑制超氧化物歧化酶 2（SOD2）活性。此外，我们的数据表明，MCU 依赖性线粒体钙摄取通过 ROS 激活的 c-Jun N 末端激酶途径促进基质金属蛋白酶-2 活性和细胞迁移，从而增强 HCC 细胞体外侵袭和迁移以及肝内和远端肺转移的能力。此外，用线粒体钙缓冲蛋白 parvalbumin 处理可显著抑制 ROS 产生和 HCC 转移能力。我们的研究揭示了一种将线粒体钙动态平衡重塑与 ROS 产生联系起来的机制，并为 MCU 依赖性线粒体钙摄取在 HCC 中的促进转移作用提供了证据。我们的发现表明，线粒体钙摄取机制可能成为 HCC 转移的一种新的治疗靶点。
