Cancer Metabolism

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



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


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.


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.


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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

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.


  1. 1.

    Caruso, S., Calatayud, A. L., Pilet, J., La Bella, T., Rekik, S., Imbeaud, S. et al. Analysis of liver cancer cell lines identifies agents with likely efficacy against hepatocellular carcinoma and markers of response. Gastroenterology. 157, 760–76. (2019).

  2. 2.

    Kulik, L. & El-Serag, H. B. Epidemiology and management of hepatocellular carcinoma. Gastroenterology. 156, 477–91 e1. (2019).

  3. 3.

    Ganly, I., Makarov, V., Deraje, S., Dong, Y., Reznik, E., Seshan, V. et al. Integrated genomic analysis of hurthle cell cancer reveals oncogenic drivers, recurrent mitochondrial mutations, and unique chromosomal landscapes. Cancer Cell. 34, 256–70 e5 (2018).

  4. 4.

    Lee, K. S., Huh, S., Lee, S., Wu, Z., Kim, A. K., Kang, H. Y. et al. Altered ER-mitochondria contact impacts mitochondria calcium homeostasis and contributes to neurodegeneration in vivo in disease models. Proc. Natl Acad. Sci. USA 115, E8844–E53. (2018).

  5. 5.

    Salimi, A., Roudkenar, M. H., Sadeghi, L., Mohseni, A., Seydi, E., Pirahmadi, N. et al. Ellagic acid, a polyphenolic compound, selectively induces ROS-mediated apoptosis in cancerous B-lymphocytes of CLL patients by directly targeting mitochondria. Redox Biol. 6, 461–71. (2015).

  6. 6.

    Chaanine, A. H., Joyce, L. D., Stulak, J. M., Maltais, S., Joyce, D. L., Dearani, J. A. et al. Mitochondrial morphology, dynamics, and function in human pressure overload or ischemic heart disease with preserved or reduced ejection fraction. Circ. Heart Fail. 12, e005131 (2019).

  7. 7.

    Simula, L., Nazio, F. & Campello, S. The mitochondrial dynamics in cancer and immune-surveillance. Semin Cancer Biol. 47, 29–42 (2017).

  8. 8.

    Zhang, J., Zhang, Y., Wu, W., Wang, F., Liu, X., Shui, G. et al. Guanylate-binding protein 2 regulates Drp1-mediated mitochondrial fission to suppress breast cancer cell invasion. Cell Death Dis. 8, e3151 (2017).

  9. 9.

    Kim, Y. Y., Yun, S. H. & Yun, J. Downregulation of Drp1, a fission regulator, is associated with human lung and colon cancers. Acta Biochim. Biophys. Sin (Shanghai) 50, 209–15. (2018).

  10. 10.

    Rehman, J., Zhang, H. J., Toth, P. T., Zhang, Y., Marsboom, G., Hong, Z. et al. Inhibition of mitochondrial fission prevents cell cycle progression in lung cancer. FASEB J. 26, 2175–2186 (2012).

  11. 11.

    Zhao, J., Zhang, J., Yu, M., Xie, Y., Huang, Y., Wolff, D. W. et al. Mitochondrial dynamics regulates migration and invasion of breast cancer cells. Oncogene. 32, 4814–4824 (2013).

  12. 12.

    Huang, Q., Zhan, L., Cao, H., Li, J., Lyu, Y., Guo, X. et al. Increased mitochondrial fission promotes autophagy and hepatocellular carcinoma cell survival through the ROS-modulated coordinated regulation of the NFKB and TP53 pathways. Autophagy. 12, 999–1014 (2016).

  13. 13.

    Huang, Q., Cao, H., Zhan, L., Sun, X., Wang, G., Li, J. et al. Mitochondrial fission forms a positive feedback loop with cytosolic calcium signaling pathway to promote autophagy in hepatocellular carcinoma cells. Cancer Lett. 403, 108–18. (2017).

  14. 14.

    Sun, X., Cao, H., Zhan, L., Yin, C., Wang, G., Liang, P. et al. Mitochondrial fission promotes cell migration by Ca(2+) /CaMKII/ERK/FAK pathway in hepatocellular carcinoma. Liver Int. 38, 1263–72. (2018).

  15. 15.

    Koppenol, W. H., Bounds, P. L. & Dang, C. V. Otto Warburg’s contributions to current concepts of cancer metabolism. Nat Rev. Cancer 11, 325–337 (2011).

  16. 16.

    Liberti, M. V. & Locasale, J. W. The Warburg effect: how does it benefit cancer cells? Trends Biochem. Sci. 41, 211–218 (2016).

  17. 17.

    Jiang, S. H., Li, J., Dong, F. Y., Yang, J. Y., Liu, D. J., Yang, X. M. et al. Increased serotonin signaling contributes to the warburg effect in pancreatic tumour cells under metabolic stress and promotes growth of pancreatic tumours in mice. Gastroenterology. 153, 277–91 e19. (2017).

  18. 18.

    Ye, Q. H., Zhu, W. W., Zhang, J. B., Qin, Y., Lu, M., Lin, G. L. et al. GOLM1 modulates EGFR/RTK cell-surface recycling to drive hepatocellular carcinoma metastasis. Cancer Cell. 30, 444–58. (2016).

  19. 19.

    Zheng, Y., Zhou, C., Yu, X. X., Wu, C., Jia, H. L., Gao, X. M. et al. Osteopontin promotes metastasis of intrahepatic cholangiocarcinoma through recruiting MAPK1 and mediating Ser675 phosphorylation of beta-Catenin. Cell Death Dis. 9, 179 (2018).

  20. 20.

    Buck, M. D., O’Sullivan, D., Klein Geltink, R. I., Curtis, J. D., Chang, C. H., Sanin, D. E. et al. Mitochondrial dynamics controls T cell fate through metabolic programming. Cell. 166, 63–76 (2016).

  21. 21.

    Zhu, Y., Yang, J., Xu, D., Gao, X. M., Zhang, Z., Hsu, J. L. et al. Disruption of tumour-associated macrophage trafficking by the osteopontin-induced colony-stimulating factor-1 signalling sensitises hepatocellular carcinoma to anti-PD-L1 blockade. Gut. 68, 1653–66. (2019).

  22. 22.

    Yang, X., Zhang, X. F., Lu, X., Jia, H. L., Liang, L., Dong, Q. Z. et al. MicroRNA-26a suppresses angiogenesis in human hepatocellular carcinoma by targeting hepatocyte growth factor-cMet pathway. Hepatology. 59, 1874–1885 (2014).

  23. 23.

    Dongre, A. & Weinberg, R. A. New insights into the mechanisms of epithelial-mesenchymal transition and implications for cancer. Nat Rev. Mol. Cell Biol. 20, 69–84 (2019).

  24. 24.

    Kannan, A., Wells, R. B., Sivakumar, S., Komatsu, S., Singh, K. P., Samten, B. et al. Mitochondrial reprogramming regulates breast cancer progression. Clin Cancer Res. 22, 3348–3360 (2016).

  25. 25.

    Dumas, J. F., Brisson, L., Chevalier, S., Maheo, K., Fromont, G., Moussata, D. et al. Metabolic reprogramming in cancer cells, consequences on pH and tumour progression: Integrated therapeutic perspectives with dietary lipids as adjuvant to anticancer treatment. Semin. Cancer Biol. 43, 90–110 (2017).

  26. 26.

    Abate M., Festa A., Falco M., Lombardi A., Luce A., Grimaldi A., et al. Mitochondria as playmakers of apoptosis, autophagy and senescence. Semin. Cell Dev. Biol. 2019.

  27. 27.

    Caino, M. C. & Altieri, D. C. Molecular pathways: mitochondrial reprogramming in tumour progression and therapy. Clin. Cancer Res. 22, 540–545 (2016).

  28. 28.

    Archer, S. L. Mitochondrial fission and fusion in human diseases. N. Engl. J Med. 370, 1074 (2014).

  29. 29.

    Valcarcel-Jimenez, L., Gaude, E., Torrano, V., Frezza, C. & Carracedo, A. Mitochondrial metabolism: Yin and Yang for tumour progression. Trends Endocrinol. Metab. 28, 748–57. (2017).

  30. 30.

    Idelchik, M., Begley, U., Begley, T. J. & Melendez, J. A. Mitochondrial ROS control of cancer. Semin. Cancer Biol. 47, 57–66 (2017).

  31. 31.

    Santidrian, A. F., Matsuno-Yagi, A., Ritland, M., Seo, B. B., LeBoeuf, S. E., Gay, L. J. et al. Mitochondrial complex I activity and NAD+/NADH balance regulate breast cancer progression. J. Clin. Invest. 123, 1068–1081 (2013).

  32. 32.

    Mourier, A., Motori, E., Brandt, T., Lagouge, M., Atanassov, I., Galinier, A. et al. Mitofusin 2 is required to maintain mitochondrial coenzyme Q levels. J. Cell Biol. 208, 429–442 (2015).

  33. 33.

    Wasilewski, M., Semenzato, M., Rafelski, S. M., Robbins, J., Bakardjiev, A. I. & Scorrano, L. Optic atrophy 1-dependent mitochondrial remodeling controls steroidogenesis in trophoblasts. Curr. Biol. 22, 1228–1234 (2012).

  34. 34.

    Qian, W., Wang, J. & Van Houten, B. The role of dynamin-related protein 1 in cancer growth: a promising therapeutic target? Expert Opin. Ther. Targets 17, 997–1001 (2013).

  35. 35.

    Sehrawat, A., Samanta, S. K., Hahm, E. R., St Croix, C., Watkins, S. & Singh, S. V. Withaferin A-mediated apoptosis in breast cancer cells is associated with alterations in mitochondrial dynamics. Mitochondrion. 47, 282–93. (2019).

  36. 36.

    Strack, S., Wilson, T. J. & Cribbs, J. T. Cyclin-dependent kinases regulate splice-specific targeting of dynamin-related protein 1 to microtubules. J. Cell Biol. 201, 1037–1051 (2013).

  37. 37.

    Vaquero, J., Guedj, N., Claperon, A., Nguyen Ho-Bouldoires, T. H., Paradis, V. & Fouassier, L. Epithelial-mesenchymal transition in cholangiocarcinoma: from clinical evidence to regulatory networks. J. Hepatol. 66, 424–41. (2017).

  38. 38.

    Qian, Y., Yao, W., Yang, T., Yang, Y., Liu, Y., Shen, Q. et al. aPKC-iota/P-Sp1/Snail signaling induces epithelial-mesenchymal transition and immunosuppression in cholangiocarcinoma. Hepatology. 66, 1165–82. (2017).

  39. 39.

    Cho, S. J., Yoon, C., Lee, J. H., Chang, K. K., Lin, J. X., Kim, Y. H. et al. KMT2C mutations in diffuse-type gastric adenocarcinoma promote epithelial-to-mesenchymal transition. Clin. Cancer Res. 24, 6556–69. (2018).

  40. 40.

    Sjoberg, E., Meyrath, M., Milde, L., Herrera, M., Lovrot, J., Hagerstrand, D. et al. A novel ACKR2-dependent role of fibroblast-derived CXCL14 in epithelial-to-mesenchymal transition and metastasis of breast cancer. Clin. Cancer Res. 25, 3702–17. (2019).

  41. 41.

    Dupuy, F., Tabaries, S., Andrzejewski, S., Dong, Z., Blagih, J., Annis, M. G. et al. PDK1-dependent metabolic reprogramming dictates metastatic potential in breast cancer. Cell Metab. 22, 577–589 (2015).

  42. 42.

    Dasgupta, S., Rajapakshe, K., Zhu, B., Nikolai, B. C., Yi, P., Putluri, N. et al. Metabolic enzyme PFKFB4 activates transcriptional coactivator SRC-3 to drive breast cancer. Nature. 556, 249–54. (2018).

  43. 43.

    Wu, Z., Wei, D., Gao, W., Xu, Y., Hu, Z., Ma, Z. et al. TPO-induced metabolic reprogramming drives liver metastasis of colorectal cancer CD110+ tumour-initiating cells. Cell Stem Cell 17, 47–59 (2015).

  44. 44.

    Jackson, J. G. & Robinson, M. B. Regulation of mitochondrial dynamics in astrocytes: Mechanisms, consequences, and unknowns. Glia. 66, 1213–1234 (2018).

  45. 45.

    Chen, H. & Chan, D. C. Mitochondrial dynamics in regulating the unique phenotypes of cancer and stem cells. Cell Metab. 26, 39–48 (2017).

Download references

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.

Ethics declarations

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.

Consent to publish

No consent was involved in this publication.

Data availability

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).

Additional information

Note This work is published under the standard license to publish agreement. After 12 months the work will become freely available and the license terms will switch to a Creative Commons Attribution 4.0 International (CC BY 4.0).

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

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).

Download citation

Further reading