Cancer Metabolism

MFN1-dependent alteration of mitochondrial dynamics drives hepatocellular carcinoma metastasis by glucose metabolic reprogramming

Abstract

Background

Mitochondrial dynamics plays an important role in tumour progression. However, how these dynamics integrate tumour metabolism in hepatocellular carcinoma (HCC) metastasis is still unclear.

Methods

The mitochondrial fusion protein mitofusin-1 (MFN1) expression and its prognostic value are detected in HCC. The effects and underlying mechanisms of MFN1 on HCC metastasis and metabolic reprogramming are analysed both in vitro and in vivo.

Results

Mitochondrial dynamics, represented by constant fission and fusion, are found to be associated with HCC metastasis. High metastatic HCC displays excessive mitochondrial fission. Among genes involved in mitochondrial dynamics, MFN1 is identified as a leading downregulated candidate that is closely associated with HCC metastasis and poor prognosis. While promoting mitochondrial fusion, MFN1 inhibits cell proliferation, invasion and migration capacity both in vitro and in vivo. Mechanistically, disruption of mitochondrial dynamics by depletion of MFN1 triggers the epithelial-to-mesenchymal transition (EMT) of HCC. Moreover, MFN1 modulates HCC metastasis by metabolic shift from aerobic glycolysis to oxidative phosphorylation. Treatment with glycolytic inhibitor 2-Deoxy-d-glucose (2-DG) significantly suppresses the effects induced by depletion of MFN1.

Conclusions

Our results reveal a critical involvement of mitochondrial dynamics in HCC metastasis via modulating glucose metabolic reprogramming. MFN1 may serve as a novel potential therapeutic target for HCC.

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Fig. 1: Mitochondrial dynamics in HCC cell lines with different metastatic potential.
Fig. 2: Low MFN1 level in human HCC was correlated with vascular invasion and poor prognosis.
Fig. 3: Increased mitochondrial fusion mediated by MFN1 inhibits migration and invasion of HCC cells in vitro.
Fig. 4: Increased mitochondrial fusion mediated by MFN1 inhibits proliferation and metastasis of HCC cells in vivo.
Fig. 5: Metabolic reprogramming in HCC cells mediated by MFN1.
Fig. 6: MFN1 influences HCC cells proliferation, invasion and migration via metabolic reprogramming.

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Author information

L-X.Q., Q-Z.D., S.G. and Z.Z. designed research; Z.Z., T-E.L., M.C., D.X., Y.Z., B-Y.H., Z.-F.L. and X.W. performed research; Z.Z. and J.-J.P. analysed data; C.W., Y.Z., L.L. and H-L.J. supervised research; Z.Z., T-E.L. and M.C. drafted the paper; L-X.Q., Q-Z.D. and S.G. revised the paper; all authors approved the paper.

Correspondence to Song Gao or Qiong-Zhu Dong or Lun-Xiu Qin.

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Ethics approval and consent to participate

Clinical samples from patients were obtained after acquiring consent of patients in accordance with the protocol approved by the Ethics Boards of Huashan Hospital of Fudan University (Shanghai, China). This study was performed in accordance with the Declaration of Helsinki. All experimental procedures in animal work were approved by the Ethical Committee of Huashan Hospital of Fudan University (Shanghai, China). Animal welfare was closely monitored in accordance with the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health.

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All data and materials generated during and/or analysed during this study are available from the corresponding author on reasonable request.

Competing interests

The authors declare no competing interests.

Funding information

This work was supported by the following: The National Key Research and Development Program of China (2017YFC1308604, 2018YFA0508300); the National Key Basic Research Program of China (2014CB542101 and 2013CB910500); National Natural Science Foundation of China (81930074, 81672820, 81772563 and 31722016).

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Zhang, Z., Li, T., Chen, M. et al. MFN1-dependent alteration of mitochondrial dynamics drives hepatocellular carcinoma metastasis by glucose metabolic reprogramming. Br J Cancer 122, 209–220 (2020). https://doi.org/10.1038/s41416-019-0658-4

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