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MCU-dependent mitochondrial Ca2+ inhibits NAD+/SIRT3/SOD2 pathway to promote ROS production and metastasis of HCC cells

Oncogene volume 36, pages 5897–5909 (2017)Cite this article

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Abstract

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.

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Abbreviations

HCC:

hepatocellular carcinoma

MCU:

mitochondrial calcium uniporter

MICU1,2:

mitochondrial calcium uptake 1,2

EMRE:

essential MCU regulator

MAPK:

mitogen-activated protein kinase

ROS:

reactive oxygen specie

PV:

parvalbumin

NAD:

nicotinamide adenine dinucleotide

NAM:

nicotinamide

PDH:

pyruvate dehydrogenase

IDH:

isocitrate dehydrogenase

α-KGDH:

α-ketoglutarate dehydrogenase

SOD2:

superoxide dismutase 2

SIRT3:

sirtuin 3

JNK:

c-Jun N-terminal kinase

MMP:

matrix metalloproteinase.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (grants 81572727 and 81320108021) and National Basic Research Program (grant 2015CB553703).

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  1. T Ren and H Zhang: These authors contributed equally to this work.

Authors and Affiliations

  1. State Key Laboratory of Cancer Biology and Experimental Teaching Center of Basic Medicine, Fourth Military Medical University, Xi’an, China

    T Ren, J Wang, J Zhu, M Jin, Y Wu, X Guo, L Ji, Q Huang & J Xing

  2. Department of Pain Treatment, Tangdu Hospital, Fourth Military Medical University, Xi'an, China

    H Zhang & H Zhang

  3. Division of Population Science, Department of Medical Oncology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA

    H Yang

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Ren, T., Zhang, H., Wang, J. et al. MCU-dependent mitochondrial Ca2+ inhibits NAD+/SIRT3/SOD2 pathway to promote ROS production and metastasis of HCC cells. Oncogene 36, 5897–5909 (2017). https://doi.org/10.1038/onc.2017.167

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