Cancer and Metastasis Reviews

, Volume 37, Issue 4, pp 643–653 | Cite as

Metabolic reprogramming of mitochondrial respiration in metastatic cancer

  • P. M. Herst
  • C. Grasso
  • Michael V. BerridgeEmail author


Tumor initiation, progression, and metastasis are tissue context-dependent processes. Cellular and non-cellular factors provide the selective microenvironment that determines the fate of the evolving tumor through mechanisms that include metabolic reprogramming. Genetic and epigenetic changes contribute to this reprogramming process, which is orchestrated through ongoing communication between the mitochondrial and nuclear genomes. Metabolic flexibility, in particular the ability to rapidly adjust the balance between glycolytic and mitochondrial energy production, is a hallmark of aggressive, invasive, and metastatic cancers. Tumor cells sustain damage to both nuclear and mitochondrial DNA during tumorigenesis and as a consequence of anticancer treatments. Nuclear and mitochondrial DNA mutations and polymorphisms are increasingly recognized as factors that influence metabolic reprogramming, tumorigenesis, and tumor progression. Severe mitochondrial DNA damage compromises mitochondrial respiration. When mitochondrial respiration drops below a cell-specific threshold, metabolic reprogramming and plasticity fail to compensate and tumor formation is compromised. In these scenarios, tumorigenesis can be restored by acquisition of respiring mitochondria from surrounding stromal cells. Thus, intercellular mitochondrial transfer has the potential to confer treatment resistance and to promote tumor progression and metastasis. Understanding the constraints of metabolic, and in particular bioenergetic reprogramming, and the role of intercellular mitochondrial transfer in tumorigenesis provides new insights into addressing tumor progression and treatment resistance in highly aggressive cancers.


Mitochondrial DNA Respiration Glycolysis Metabolic reprogramming Intercellular mitochondrial transfer 



We acknowledge unpublished mouse tumor mtDNA sequence information from Matt Rowe and Georgia Carson.

Authors’ contributions

MVB and PH planned and wrote the review; CG prepared Table 1, contributed to Fig. 1 and to parts of the text, and all authors contributed to editing and revision.

Funding information

The authors received author salary support from the Health Research Council of NZ, the Cancer Society of NZ, the Malaghan Institute (MVB, CG) and the University of Otago, Wellington (PH).


  1. 1.
    Wu, F., & Minteer, S. (2015). Krebs cycle metabolon: Structural evidence of substrate channeling revealed by cross-linking and mass spectrometry. Angewandte Chemie, International Edition, 54(6), 1851–1854.Google Scholar
  2. 2.
    Ahn, C., & Metallo, C. (2015). Mitochondria as biosynthetic factories for cancer proliferation. Cancer & Metabolism, 3(1), 1–10.Google Scholar
  3. 3.
    Smolková, K., Plecitá-Hlavatá, L., Bellance, N., Benard, G., Rossignol, R., & Ježek, P. (2011). Waves of gene regulation suppress and then restore oxidative phosphorylation in cancer cells. The International Journal of Biochemistry & Cell Biology, 43(7), 950–968.Google Scholar
  4. 4.
    Wallace, D., Fan, W., & Procaccio, V. (2010). Mitochondrial energetics and therapeutics. Annual Review of Pathology, 5, 297–348.Google Scholar
  5. 5.
    Wallace, D. (2016). Mitochondrial DNA in aging and disease. Nature, 535(7613), 498–500.Google Scholar
  6. 6.
    Coppotelli, G., & Ross, J. (2016). Mitochondria in Ageing and Diseases: The Super Trouper of the Cell. International Journal of Molecular Sciences, 17(5), 711 (1–5).Google Scholar
  7. 7.
    Deberardinis, R., & Chandel, N. (2016). Fundamentals of cancer metabolism. Oncology, 2(5), e1600200.Google Scholar
  8. 8.
    Halestrap, A., & Richardson, A. (2015). The mitochondrial permeability transition: A current perspective on its identity and role in ischaemia/reperfusion injury. Journal of Molecular and Cellular Cardiology, 78, 129–141.Google Scholar
  9. 9.
    Simula, L., Nazio, F., & Campello, S. (2017). The mitochondrial dynamics in cancer and immune-surveillance. Seminars in Cancer Biology, 47(December 2016), 29–42.Google Scholar
  10. 10.
    Giorgi, C., Missiroli, S., Patergnani, S., Duszynski, J., Wieckowski, M., & Pinton, P. (2015). Mitochondria-associated membranes: Composition, molecular mechanisms, and Physiopathological implications. Antioxidants & Redox Signaling, 22(12), 995–1019.Google Scholar
  11. 11.
    Missiroli, S., Patergnani, S., Caroccia, N., Pedriali, G., Perrone, M., Previati, M., et al. (2018). Mitochondria-associated membranes (MAMs) and inflammation. Cell Death & Disease, 9(3), 329.Google Scholar
  12. 12.
    Wang, J., Liu, X., Qiu, Y., Shi, Y., Cai, J., Wang, B., Wei, X., Ke, Q., Sui, X., Wang, Y., Huang, Y., Li, H., Wang, T., Lin, R., Liu, Q., & Xiang, A. P. (2018). Cell adhesion-mediated mitochondria transfer contributes to mesenchymal stem cell-induced chemoresistance on T cell acute lymphoblastic leukemia cells. Journal of Hematology & Oncology, 11(1), 1–13.Google Scholar
  13. 13.
    Gottlieb, R., & Stotland, A. (2015). MitoTimer: A novel protein for monitoring mitochondrial turnover in the heart. Journal of Molecular Medicine, 93(3), 271–278.Google Scholar
  14. 14.
    Youle, R., & Narendra, D. (2011). Mechanisms of mitophagy. Nature Reviews. Molecular Cell Biology, 12(1), 9–14.Google Scholar
  15. 15.
    Taanman, J.-W. (1999). The mitochondrial genome: Structure, transcription, translation and replication. Biochimica et Biophysica Acta, Bioenergetics, 1410, 103–123.Google Scholar
  16. 16.
    Hensen, F., Cansiz, S., Gerhold, J., & Spelbrink, J. (2014). To be or not to be a nucleoid protein: A comparison of mass-spectrometry based approaches in the identification of potential mtDNA-nucleoid associated proteins. Biochimie, 100(1), 219–226.Google Scholar
  17. 17.
    Arnould, T., Michel, S., & Renard, P. (2015). Mitochondria retrograde signaling and the UPR mt: Where are we in mammals? International Journal of Molecular Sciences, 16(8), 18224–18251.Google Scholar
  18. 18.
    Mookerjee, S. A., Gerencser, A. A., Nicholls, D. G., & Brand, M. D. (2017). Quantifying intracellular rates of glycolytic and oxidative ATP production and consumption using extracellular flux measurements. The Journal of Biological Chemistry, 292(17), 7189–7207.Google Scholar
  19. 19.
    Herst, P. M., Tan, A. S., Scarlett, D.-J. G., & Berridge, M. V. (2004). Cell surface oxygen consumption by mitochondrial gene knockout cells. Biochimica et Biophysica Acta, 1656(2–3), 79–87.Google Scholar
  20. 20.
    Herst, P., & Berridge, M. (2007). Cell surface oxygen consumption: A major contributor to cellular oxygen consumption in glycolytic cancer cell lines. Biochimica et Biophysica Acta, Bioenergetics, 1767(2), 170–177.Google Scholar
  21. 21.
    Herst, P., & Berridge, M. (2006). Plasma membrane electron transport: A new target for cancer drug development. Current Molecular Medicine, 6, 895–904.Google Scholar
  22. 22.
    Scarlett, D., Herst, P., Tan, A., Prata, C., & Berridge, M. (2004). Mitochondrial gene-knockout (rho0) cells: A versatile model for exploring the secrets of trans-plasma membrane electron transport. BioFactors, 20(4), 199–206.Google Scholar
  23. 23.
    Courtnay, R., Ngo, D., Malik, N., Ververis, K., Tortorella, S., & Karagiannis, T. (2015). Cancer metabolism and the Warburg effect: The role of HIF-1 and PI3K. Molecular Biology Reports, 42(4), 841–851.Google Scholar
  24. 24.
    Guerra, F., Arbini, A., & Moro, L. (2017). Mitochondria and cancer chemoresistance. Biochimica et Biophysica Acta, Bioenergetics, 1858(8), 686–699.Google Scholar
  25. 25.
    Quinlan, C., Perevoshchikova, I., Orr, A., & Brand, M. (2013). Sites of reactive oxygen species generation by mitochondria oxidizing different substrates. Redox Biology, 1(1), 304–312.Google Scholar
  26. 26.
    Chen, Y., Zhang, H., Zhou, H., Ji, W., & Min, W. (2016). Mitochondrial redox signaling and tumor progression. Cancers (Basel)., 8(4), 1–15.Google Scholar
  27. 27.
    Holzerová, E., & Prokisch, H. (2015). Mitochondria: Much ado about nothing? How dangerous is reactive oxygen species production? The International Journal of Biochemistry & Cell Biology, 63, 16–20.Google Scholar
  28. 28.
    Dikalov, S. (2011). Crosstalk between mitochondria and NADPH oxidases. Free Radical Biology & Medicine, 51(7), 1289–1301.Google Scholar
  29. 29.
    Warburg, O. (1956). On the origin of cancer ells. Nature, 123(3191), 309–314.Google Scholar
  30. 30.
    Heiden Vander, M. G., Cantley, L., & Thompson, C. (2009). Understanding the Warburg Effect : Cell Proliferation. Science, 324(May), 1029.Google Scholar
  31. 31.
    Gatenby, R., & Gillies, R. (2004). Why do cancers have high aerobic glycolysis? Nature Reviews Cancer, 4(11), 891–899.Google Scholar
  32. 32.
    Porporato, P., Payen, V., Pérez-Escuredo, J., De Saedeleer, C., Danhier, P., Copetti, T., et al. (2014). A mitochondrial switch promotes tumor metastasis. Cell Reports, 8(3), 754–766.Google Scholar
  33. 33.
    Carelli, V., Maresca, A., Caporali, L., Trifunov, S., Zanna, C., & Rugolo, M. (2015). Mitochondria: Biogenesis and mitophagy balance in segregation and clonal expansion of mitochondrial DNA mutations. The International Journal of Biochemistry & Cell Biology, 63, 21–24.Google Scholar
  34. 34.
    Busch, K., Kowald, A., & Spelbrink, J. (2014). Quality matters: How does mitochondrial network dynamics and quality control impact on mtDNA integrity? Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences, 369(1646), 20130442.Google Scholar
  35. 35.
    Gumeni, S., & Trougakos, I. (2016). Cross talk of Proteostasis and Mitostasis in cellular Homeodynamics, ageing, and disease. Oxidative Medicine and Cellular Longevity, 2016, 1–24.Google Scholar
  36. 36.
    Sun, X., & St. John, J. C. (2016). The role of the mtDNA set point in differentiation, development and tumorigenesis. The Biochemical Journal, 473(19), 2955–2971.Google Scholar
  37. 37.
    van Gisbergen, M. W., Voets, A. M., Starmans, M. H. W., de Coo, I. F. M., Yadak, R., Hoffmann, R. F., Boutros, P. C., Smeets, H. J. M., Dubois, L., & Lambin, P. (2015). How do changes in the mtDNA and mitochondrial dysfunction influence cancer and cancer therapy? Challenges, opportunities and models. Mutation Research, Reviews in Mutation Research, 764, 16–30.Google Scholar
  38. 38.
    Picard, M., Wallace, D. C., & Burelle, Y. (2016). The rise of mitochondria in medicine. Mitochondrion, 30, 105–116.Google Scholar
  39. 39.
    Singh, B., Modica-Napolitano, J., & Singh, K. (2017). Defining the momiome: Promiscuous information transfer by mobile mitochondria and the mitochondrial genome. Seminars in Cancer Biology, 47(April), 1–17.Google Scholar
  40. 40.
    Tuppen, H., Blakely, E., Turnbull, D., & Taylor, R. (2010). Mitochondrial DNA mutations and human disease. Biochimica et Biophysica Acta, 1797(2), 113–128.Google Scholar
  41. 41.
    Garrido, N., Griparic, L., Jokitalo, E., Wartiovaara, J., van der Bliek, A., & Spelbrink, J. N. (2003). Composition and dynamics of human mitochondrial nucleoids. Molecular Biology of the Cell, 14(4), 1583–1596.Google Scholar
  42. 42.
    Guliaeva, N., Kuznetsova, E., & Gaziev, A. (2006). Proteins associated with mitochon- drial DNA protect it against the action of X-rays and hydrogen peroxide. Biofizika, 51(4), 692–697.Google Scholar
  43. 43.
    Twig, G., & Shirihai, O. G. (2011). The interplay between mitochondrial dynamics and mitophagy. Antioxidants & Redox Signaling, 14(10), 1939–1951.Google Scholar
  44. 44.
    Iommarini, L., Kurelac, I., Capristo, M., Calvaruso, M., Giorgio, V., Bergamini, C., et al. (2014). Different mtDNA mutations modify tumor progression in dependence of the degree of respiratory complex I impairment. Human Molecular Genetics, 23(6), 1453–1466.Google Scholar
  45. 45.
    Wallace, D., & Mitochondrial, D. N. A. (2015). Variation in human radiation and disease. Cell, 163(1), 33–38.Google Scholar
  46. 46.
    Kenney, M. C., Chwa, M., Atilano, S. R., Falatoonzadeh, P., Ramirez, C., Malik, D., Tarek, M., del Carpio, J. C., Nesburn, A. B., Boyer, D. S., Kuppermann, B. D., Vawter, M. P., Jazwinski, S. M., Miceli, M. V., Wallace, D. C., & Udar, N. (2014). Molecular and bioenergetic differences between cells with African versus European inherited mitochondrial DNA haplogroups: Implications for population susceptibility to diseases. Biochimica et Biophysica Acta, Molecular Basis of Disease, 1842(2), 208–219.Google Scholar
  47. 47.
    Ishikawa, K., Takenaga, K., Akimoto, M., Koshikawa, N., Yamaguchi, A., Imanishi, H., et al. (2008). ROS-Generating Mitochondrial DNA Mutations Can Regulate Tumor Cell Metastasis. Science, 320(5876), 661–664.Google Scholar
  48. 48.
    Tan, A., Baty, J., Dong, L., Bezawork-Geleta, A., Endaya, B., Goodwin, J., et al. (2015). Mitochondrial genome acquisition restores respiratory function and tumorigenic potential of cancer cells without mitochondrial DNA. Cell Metabolism, 21(1), 81–94.Google Scholar
  49. 49.
    Bayona-Bafaluy, M., Acín-Pérez, R., Mullikin, J., Park, J., Moreno-Loshuertos, R., Hu, P., et al. (2003). Revisiting the mouse mitochondrial DNA sequence. Nucleic Acids Research, 31(18), 5349–5355.Google Scholar
  50. 50.
    Brinker, A., Vivian, C., Koestler, D., Tsue, T., Jensen, R., & Welch, D. (2017). Mitochondrial haplotype alters mammary cancer tumorigenicity and metastasis in an oncogenic driver–dependent manner. Cancer Research, 77(24), 6941–6949.Google Scholar
  51. 51.
    Hunter, K., Amin, R., Deasy, S., Ha, N., & Wakefield, L. (2018). Genetic insights into the morass of metastatic heterogeneity. Nature Reviews Cancer, 18(4), 211–223.Google Scholar
  52. 52.
    Vivian, C., Brinker, A., Graw, S., Koestler, D., Legendre, C., Gooden, G., et al. (2017). Mitochondrial genomic backgrounds affect nuclear DNA methylation and gene expression. Cancer Research, 77(22), 6202–6214.Google Scholar
  53. 53.
    Sun, X., Johnson, J., & St John, J. (2018). Global DNA methylation synergistically regulates the nuclear and mitochondrial genomes in glioblastoma cells. Nucleic Acids Research, 46(12), 5977–5995.Google Scholar
  54. 54.
    Dong, L., Kovarova, J., Bajzikova, M., Bezawork-Geleta, A., Svec, D., Endaya, B., et al. (2017). Horizontal transfer of whole mitochondria restores tumorigenic potential in mitochondrial DNA-deficient cancer cells. eLife, 6.Google Scholar
  55. 55.
    Lee, W., Sun, X., Tsai, T.-S., Johnson, J., Gould, J., Garama, D., et al. (2017). Mitochondrial DNA haplotypes induce differential patterns of DNA methylation that result in differential chromosomal gene expression patterns. Cell Death & Disease, 3(August), 17062.Google Scholar
  56. 56.
    Danhier, P., Bański, P., Payen, V., Grasso, D., Ippolito, L., Sonveaux, P., et al. (2017). Cancer metabolism in space and time: Beyond the Warburg effect. Biochimica et Biophysica Acta, Bioenergetics, 1858(8), 556–572.Google Scholar
  57. 57.
    Jose, C., Bellance, N., & Rossignol, R. (2011). Choosing between glycolysis and oxidative phosphorylation: A tumor’s dilemma? Biochimica et Biophysica Acta, Bioenergetics, 1807(6), 552–561.Google Scholar
  58. 58.
    Ventura-Clapier, R., Garnier, A., & Veksler, V. (2008). Transcriptional control of mitochondrial biogenesis: The central role of PGC-1alpha. Cardiovascular Research, 79(2), 208–217.Google Scholar
  59. 59.
    Berridge, M., & Herst, P. (2015). Tumor cell complexity and metabolic flexibility in tumorigenesis and metastasis. In S. Mazurek & M. Shoshan (Eds.), Tumor cell metabolism (p. 23–43). Vienna: Springer.Google Scholar
  60. 60.
    Ralph, S., Rodríguez-Enríquez, S., Neuzil, J., & Moreno-Sánchez, R. (2010). Bioenergetic pathways in tumor mitochondria as targets for cancer therapy and the importance of the ROS-induced apoptotic trigger. Molecular Aspects of Medicine, 31(1), 29–59.Google Scholar
  61. 61.
    Herst, P., Dawson, R., & Berridge, M. (2018). Intercellular Communication in Tumor Biology: A Role for Mitochondrial Transfer. Frontiers in Oncology, 8(August), 344.Google Scholar
  62. 62.
    Spees, J., Lee, R., & Gregory, C. (2016). Mechanisms of mesenchymal stem/stromal cell function. Stem Cell Research & Therapy, 7(1), 125.Google Scholar
  63. 63.
    Su, S., Chen, J., Yao, H., Liu, J., Yu, S., Lao, L., et al. (2018). CD10+GPR77+Cancer-Associated Fibroblasts Promote Cancer Formation and Chemoresistance by Sustaining Cancer Stemness. Cell, 172(4), 841–856.e16.Google Scholar
  64. 64.
    LeBleu, V., & Kalluri, R. (2018). A peek into cancer-associated fibroblasts: origins, functions and translational impact. Disease Models & Mechanisms, 11(4), dmm029447.Google Scholar
  65. 65.
    Kalluri, R. (2016). The biology and function of fibroblasts in cancer. Nature Reviews. Cancer, 16(9), 582–598.Google Scholar
  66. 66.
    Costa, A., Kieffer, Y., Scholer-Dahirel, A., Pelon, F., Bourachot, B., Cardon, M., et al. (2018). Fibroblast Heterogeneity and Immunosuppressive Environment in Human Breast Cancer. Cancer Cell, 33(3), 463–479.e10.Google Scholar
  67. 67.
    Liao, Z., Tan, Z., Zhu, P., & Tan, N. (2018). Cancer-associated fibroblasts in tumor microenvironment - accomplices in tumor malignancy. Cellular Immunology, (September 2017), 0–1.Google Scholar
  68. 68.
    Barnes, T., & Amir, E. (2017). HYPE or HOPE: The prognostic value of infiltrating immune cells in cancer. British Journal of Cancer, 117(4), 451–460.Google Scholar
  69. 69.
    King, M. P., & Attardi, G. (1989). Human cells lacking mtDNA: Repopulation with exogenous mitochondria by complementation. Science, 246(4929), 500–503.Google Scholar
  70. 70.
    Larm, J. A., Vaillant, F., Linnane, A. W., & Lawen, A. (1994). Up-regulation of the plasma membrane oxidoreductase as a prerequisite for viability of human Nawala Ro cells. The Journal of Biological Chemistry, 269, 30097–30100.Google Scholar
  71. 71.
    Spees, J., Olson, S., Whitney, M., & Prockop, D. (2006). Mitochondrial transfer between cells can rescue aerobic respiration. Proceedings of the National Academy of Sciences, 103(5), 1283–1288.Google Scholar
  72. 72.
    Berridge, M., Dong, L., & Neuzil, J. (2015). Mitochondrial DNA in tumor initiation, progression, and metastasis: Role of horizontal mtDNA transfer. Cancer Research, 75(16), 3203–3208.Google Scholar
  73. 73.
    Rodriguez, A., Nakhle, J., Griessinger, E., & Vignais, M. (2018). Intercellular mitochondria trafficking highlighting the dual role of mesenchymal stem cells as both sensors and rescuers of tissue injury. Cell Cycle, 17(6), 712–721.Google Scholar
  74. 74.
    Berridge, M. V., & Tan, A. S. (2010). Effects of mitochondrial gene deletion on tumorigenicity of metastatic melanoma: Reassessing the Warburg effect. Rejuvenation Research, 13(2–3), 139–141.Google Scholar
  75. 75.
    Caicedo, A., Fritz, V., Brondello, J.-M., Ayala, M., Dennemont, I., Abdellaoui, N., de Fraipont, F., Moisan, A., Prouteau, C. A., Boukhaddaoui, H., Jorgensen, C., & Vignais, M. L. (2015). MitoCeption as a new tool to assess the effects of mesenchymal stem/stromal cell mitochondria on cancer cell metabolism and function. Scientific Reports, 5(1), 9073.Google Scholar
  76. 76.
    Davis, C., Kim, K.-Y., Bushong, E., Mills, E., Boassa, D., Shih, T., et al. (2014). Transcellular degradation of axonal mitochondria. Proceedings of the National Academy of Sciences of the United States of America, 111(26), 9633–9638.Google Scholar
  77. 77.
    Lee, W., Cain, J., Cuddihy, A., Johnson, J., Dickinson, A., Yeung, K.-Y., et al. (2016). Mitochondrial DNA plasticity is an essential inducer of tumorigenesis. Cell Death & Disease, 2(January), 16016.Google Scholar
  78. 78.
    Moschoi, R., Imbert, V., Nebout, M., Chiche, J., Mary, D., Prebet, T., Saland, E., Castellano, R., Pouyet, L., Collette, Y., Vey, N., Chabannon, C., Recher, C., Sarry, J. E., Alcor, D., Peyron, J. F., & Griessinger, E. (2016). Protective mitochondrial transfer from bone marrow stromal cells to acute myeloid leukemic cells during chemotherapy. Blood, 128, 253–264.Google Scholar
  79. 79.
    Marlein, C., Zaitseva, L., Piddock, R., Robinson, S., Edwards, D., Shafat, M., et al. (2017). NADPH oxidase-2 derived superoxide drives mitochondrial transfer from bone marrow stromal cells to leukemic blasts. Blood, 130(14), 1649–1660.Google Scholar
  80. 80.
    Kulawiec, M., Safina, A., Desouki, M., Still, I., Matsui, S.-I., Bakin, A., et al. (2008). Tumorigenic transformation of human breast epithelial cells induced by mitochondrial DNA depletion. Cancer Biology & Therapy, 7(11), 1732–1743.Google Scholar
  81. 81.
    Tran, Q., Lee, H., Park, J., Kim, S.-H., & Park, J. (2016). Targeting Cancer metabolism - revisiting the Warburg effects. Toxicology Research, 32(3), 177–193.Google Scholar

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Authors and Affiliations

  • P. M. Herst
    • 1
    • 2
  • C. Grasso
    • 1
  • Michael V. Berridge
    • 1
    Email author
  1. 1.Malaghan Institute of Medical ResearchWellingtonNew Zealand
  2. 2.Department of Radiation TherapyUniversity of OtagoWellingtonNew Zealand

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