Skip to main content

Advertisement

SpringerLink
Log in

Mitochondrial elongation-mediated glucose metabolism reprogramming is essential for tumour cell survival during energy stress

  • Original Article
  • Published:
Oncogene Submit manuscript

Abstract

To date, mechanisms of tumour cell survival under energy stress are not well understood. Cumulative evidence is beginning to reveal that specific mitochondrial morphologies are often associated with energetic states and survival of cells. However, the functional roles of mitochondria in the metabolic adaptation of tumour cells to energy stress remain to be elucidated. In this study, we first investigated the changes in mitochondrial morphology induced by nutrition deprivation in tumour cells, and the underlying molecular mechanism. We then systematically explored glucose metabolism reprogramming by energy stress-induced alteration of mitochondrial morphology and its effect on tumour cell survival. Our results showed that starvation treatment resulted in a dramatic mitochondrial elongation, which was mainly mediated by DRP1S637 phosphorylation through protein kinase A activation and subsequent suppression of mitochondrial translocation of DRP1. We further observed that tumour cells under an energy stress condition exhibited a clear shift from glycolysis towards oxidative phosphorylation, which was reversed by the recovery of mitochondrial fission induced by forced expression of mutant DRP1S637A. Mechanistically, energy stress-induced mitochondrial elongation facilitated cristae formation and assembly of respiratory complexes to enhance oxidative phosphorylation, which in turn exhibited a feedback inhibitory effect on glycolysis through NAD+-dependent SIRT1 activation. In addition, our data indicated that DRP1S637-mediated mitochondrial elongation under energy stress was essential for tumour cell survival both in vitro and in vivo and predicted poor prognosis of hepatocellular carcinoma patients. Overall, our study demonstrates that remodelling of mitochondrial morphology plays a critical role in tumour cell adaptation to energy stress by reprogramming glucose metabolism.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

Similar content being viewed by others

References

  1. Kim JW, Dang CV . Cancer’s molecular sweet tooth and the Warburg effect. Cancer Res 2006; 66: 8927–8930.

    Article  CAS  PubMed  Google Scholar 

  2. Birsoy K, Possemato R, Lorbeer FK, Bayraktar EC, Thiru P, Yucel B et al. Metabolic determinants of cancer cell sensitivity to glucose limitation and biguanides. Nature 2014; 508: 108–112.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Archer SL . Mitochondrial dynamics—mitochondrial fission and fusion in human diseases. N Engl J Med 2013; 369: 2236–2251.

    Article  CAS  PubMed  Google Scholar 

  4. Hoppins S, Lackner L, Nunnari J . The machines that divide and fuse mitochondria. Ann Rev Biochem 2007; 76: 751–780.

    Article  CAS  PubMed  Google Scholar 

  5. Taguchi N, Ishihara N, Jofuku A, Oka T, Mihara K . Mitotic phosphorylation of dynamin-related GTPase Drp1 participates in mitochondrial fission. J Biol Chem 2007; 282: 11521–11529.

    Article  CAS  PubMed  Google Scholar 

  6. Gomes LC, Di Benedetto G, Scorrano L . During autophagy mitochondria elongate, are spared from degradation and sustain cell viability. Nat Cell Biol 2011; 13: 589–598.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Molina AJ, Wikstrom JD, Stiles L, Las G, Mohamed H, Elorza A et al. Mitochondrial networking protects beta-cells from nutrient-induced apoptosis. Diabetes 2009; 58: 2303–2315.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Jakobs S, Martini N, Schauss AC, Egner A, Westermann B, Hell SW . Spatial and temporal dynamics of budding yeast mitochondria lacking the division component Fis1p. J Cell Sci 2003; 116: 2005–2014.

    Article  CAS  PubMed  Google Scholar 

  9. Mishra P, Chan DC . Metabolic regulation of mitochondrial dynamics. J Cell Biol 2016; 212: 379–387.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Chen H, Chomyn A, Chan DC . Disruption of fusion results in mitochondrial heterogeneity and dysfunction. J Biol Chem 2005; 280: 26185–26192.

    Article  CAS  PubMed  Google Scholar 

  11. Chen H, Vermulst M, Wang YE, Chomyn A, Prolla TA, McCaffery JM et al. Mitochondrial fusion is required for mtDNA stability in skeletal muscle and tolerance of mtDNA mutations. Cell 2010; 141: 280–289.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Bristow RG, Hill RP . Hypoxia and metabolism. Hypoxia, DNA repair and genetic instability. Nat Rev Cancer 2008; 8: 180–192.

    Article  CAS  PubMed  Google Scholar 

  13. Zeng W, Liu P, Pan W, Singh SR, Wei Y . Hypoxia and hypoxia inducible factors in tumor metabolism. Cancer Lett 2015; 356: 263–267.

    Article  CAS  PubMed  Google Scholar 

  14. Lim JH, Lee YM, Chun YS, Chen J, Kim JE, Park JW . Sirtuin 1 modulates cellular responses to hypoxia by deacetylating hypoxia-inducible factor 1alpha. Mol Cell 2010; 38: 864–878.

    Article  CAS  PubMed  Google Scholar 

  15. Yoon H, Shin SH, Shin DH, Chun YS, Park JW . Differential roles of Sirt1 in HIF-1alpha and HIF-2alpha mediated hypoxic responses. Biochem Biophys Res Commun 2014; 444: 36–43.

    Article  CAS  PubMed  Google Scholar 

  16. Rambold AS, Kostelecky B, Elia N, Lippincott-Schwartz J . Tubular network formation protects mitochondria from autophagosomal degradation during nutrient starvation. Proc Natl Acad Sci USA 2011; 108: 10190–10195.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Rossignol R, Gilkerson R, Aggeler R, Yamagata K, Remington SJ, Capaldi RA . Energy substrate modulates mitochondrial structure and oxidative capacity in cancer cells. Cancer Res 2004; 64: 985–993.

    Article  CAS  PubMed  Google Scholar 

  18. Toda C, Kim JD, Impellizzeri D, Cuzzocrea S, Liu ZW, Diano S . UCP2 regulates mitochondrial fission and ventromedial nucleus control of glucose responsiveness. Cell 2016; 164: 872–883.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Ikeda Y, Shirakabe A, Maejima Y, Zhai P, Sciarretta S, Toli J et al. Endogenous Drp1 mediates mitochondrial autophagy and protects the heart against energy stress. Circ Res 2015; 116: 264–278.

    Article  CAS  PubMed  Google Scholar 

  20. Ong SB, Subrayan S, Lim SY, Yellon DM, Davidson SM, Hausenloy DJ . Inhibiting mitochondrial fission protects the heart against ischemia/reperfusion injury. Circulation 2010; 121: 2012–2022.

    Article  CAS  PubMed  Google Scholar 

  21. Toyama EQ, Herzig S, Courchet J, Lewis TL Jr, Loson OC, Hellberg K et al. Metabolism. AMP-activated protein kinase mediates mitochondrial fission in response to energy stress. Science 2016; 351: 275–281.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Ferretti AC, Tonucci FM, Hidalgo F, Almada E, Larocca MC, Favre C . AMPK and PKA interaction in the regulation of survival of liver cancer cells subjected to glucose starvation. Oncotarget 2016; 7: 17815–17828.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Chang CR, Blackstone C . Cyclic AMP-dependent protein kinase phosphorylation of Drp1 regulates its GTPase activity and mitochondrial morphology. J Biol Chem 2007; 282: 21583–21587.

    Article  CAS  PubMed  Google Scholar 

  24. Loh JK, Lin CC, Yang MC, Chou CH, Chen WS, Hong MC et al. GSKIP- and GSK3-mediated anchoring strengthens cAMP/PKA/Drp1 axis signaling in the regulation of mitochondrial elongation. Biochim Biophys Acta 2015; 1853: 1796–1807.

    Article  CAS  PubMed  Google Scholar 

  25. Hardie DG, Ross FA, Hawley SA . AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nat Rev Mol Cell Biol 2012; 13: 251–262.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Liu Z, Sun Y, Tan S, Liu L, Hu S, Huo H et al. Nutrient deprivation-related OXPHOS/glycolysis interconversion via HIF-1alpha/C-MYC pathway in U251 cells. Tumour Biol: The Journal of the International Society for Oncodevelopmental Biology and Medicine 2015; 37: 6661–6671.

    Article  Google Scholar 

  27. Hong J, Kim BW, Choo HJ, Park JJ, Yi JS, Yu DM et al. Mitochondrial complex I deficiency enhances skeletal myogenesis but impairs insulin signaling through SIRT1 inactivation. J Biol Chem 2014; 289: 20012–20025.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Strauss M, Hofhaus G, Schroder RR, Kuhlbrandt W . Dimer ribbons of ATP synthase shape the inner mitochondrial membrane. EMBO J 2008; 27: 1154–1160.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Guido C, Whitaker-Menezes D, Lin Z, Pestell RG, Howell A, Zimmers TA et al. Mitochondrial fission induces glycolytic reprogramming in cancer-associated myofibroblasts, driving stromal lactate production, and early tumor growth. Oncotarget 2012; 3: 798–810.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Michan S, Sinclair D . Sirtuins in mammals: insights into their biological function. Biochem J 2007; 404: 1–13.

    Article  CAS  PubMed  Google Scholar 

  31. Imai S, Guarente L . NAD+ and sirtuins in aging and disease. Trends Cell Biol 2014; 24: 464–471.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Verdin E . The many faces of sirtuins: coupling of NAD metabolism, sirtuins and lifespan. Nat Med 2014; 20: 25–27.

    Article  CAS  PubMed  Google Scholar 

  33. Rahman S, Islam R . Mammalian Sirt1: insights on its biological functions. Cell Commun Signal 2011; 9: 11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Serasinghe MN, Wieder SY, Renault TT, Elkholi R, Asciolla JJ, Yao JL et al. Mitochondrial division is requisite to RAS-induced transformation and targeted by oncogenic MAPK pathway inhibitors. Mol Cell 2015; 57: 521–536.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Kashatus JA, Nascimento A, Myers LJ, Sher A, Byrne FL, Hoehn KL et al. Erk2 phosphorylation of Drp1 promotes mitochondrial fission and MAPK-driven tumor growth. Mol Cell 2015; 57: 537–551.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. 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 2016. 1–16.

  37. Huang Q, Li J, Xing J, Li W, Li H, Ke X et al. CD147 promotes reprogramming of glucose metabolism and cell proliferation in HCC cells by inhibiting the p53-dependent signaling pathway. J Hepatol 2014; 61: 859–866.

    Article  CAS  PubMed  Google Scholar 

  38. Xing J, Chen M, Wood CG, Lin J, Spitz MR, Ma J et al. Mitochondrial DNA content: its genetic heritability and association with renal cell carcinoma. J Natl Cancer Inst 2008; 100: 1104–1112.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Natural Science Foundation of China (grants 81320108021 and 81572304) and National Basic Research Program (grant 2015CB553703) of China.

Author information

Author notes

  1. J Li and Q Huang: 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

    J Li, Q Huang, X Long, X Guo, X Sun, Z Li, T Ren, X Huang & J Xing

  2. Department of Pharmacy, Xi’jing Hospital, Fourth Military Medical University, Xi’an, China

    X Jin

  3. Department of Pain Treatment, Tangdu Hospital, Fourth Military Medical University, Xi’an, China

    P Yuan & H Zhang

Authors
  1. J Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Q Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. X Long
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. X Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. X Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. X Jin
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Z Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. T Ren
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. P Yuan
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. X Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. H Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. J Xing
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J Xing.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, J., Huang, Q., Long, X. et al. Mitochondrial elongation-mediated glucose metabolism reprogramming is essential for tumour cell survival during energy stress. Oncogene 36, 4901–4912 (2017). https://doi.org/10.1038/onc.2017.98

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2017.98

  • Springer Nature Limited

This article is cited by

Search

Navigation