Toxicological Research

Korean Society of Toxicology & Korea Environmental Mutagen Society (한국독성학회)
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Mitochondria in Cancer Energy Metabolism: Culprits or Bystanders?

  • Kim, Aekyong (School of Pharmacy, Catholic University of Daegu)
  • Received : 2015.11.18
  • Accepted : 2015.12.17
  • Published : 2015.12.31
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Abstract

Cancer is a disease characterized by uncontrolled growth. Metabolic demands to sustain rapid proliferation must be compelling since aerobic glycolysis is the first as well as the most commonly shared characteristic of cancer. During the last decade, the significance of metabolic reprogramming of cancer has been at the center of attention. Nonetheless, despite all the knowledge gained on cancer biology, the field is not able to reach agreement on the issue of mitochondria: Are damaged mitochondria the cause for aerobic glycolysis in cancer? Warburg proposed the damaged mitochondria theory over 80 years ago; the field has been testing the theory equally long. In this review, we will discuss alterations in metabolic fluxes of cancer cells, and provide an opinion on the damaged mitochondria theory.

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References

  1. Seyfried, T.N., Flores, R.E., Poff, A.M. and D'Agostino, D.P. (2014) Cancer as a metabolic disease: implications for novel therapeutics. Carcinogenesis, 35, 515-527. https://doi.org/10.1093/carcin/bgt480
  2. Coller, H.A. (2014) Is cancer a metabolic disease? Am. J. Pathol., 184, 4-17. https://doi.org/10.1016/j.ajpath.2013.07.035
  3. Warburg, O., Wind, F. and Neglers, E. (1930) On the metabolism of tumors in the body in In metabolism of tumors Ed. Arnold Constable and Co. Press, London, pp. 254-270.
  4. Koppenol, W.H., Bounds, P.L. and Dang, C.V. (2011) Otto Warburg's contributions to current concepts of cancer metabolism. Nat. Rev. Cancer, 11, 325-337. https://doi.org/10.1038/nrc3038
  5. Crabtree, H.G. (1929) Observations on the carbohydrate metabolism of tumours. Biochem. J., 23, 536-545. https://doi.org/10.1042/bj0230536
  6. Weinhouse, S. (1956) On respiratory impairment in cancer cells. Science, 124, 267-269. https://doi.org/10.1126/science.124.3215.267
  7. Senyilmaz, D. and Teleman, A.A. (2015) Chicken or the egg: Warburg effect and mitochondrial dysfunction. F1000Prime Rep., 7, 41.
  8. Hanahan, D. and Weinberg, R.A. (2011) Hallmarks of cancer: the next generation. Cell, 144, 646-674. https://doi.org/10.1016/j.cell.2011.02.013
  9. Schwartzenberg-Bar-Yoseph, F., Armoni, M. and Karnieli, E. (2004) The tumor suppressor p53 down-regulates glucose transporters GLUT1 and GLUT4 gene expression. Cancer Res., 64, 2627-2633. https://doi.org/10.1158/0008-5472.CAN-03-0846
  10. Zhang, C., Liu, J., Liang, Y., Wu, R., Zhao, Y., Hong, X., Lin, M., Yu, H., Liu, L., Levine, A.J., Hu, W. and Feng, Z. (2013) Tumour-associated mutant p53 drives the Warburg effect. Nat. Commun., 4, 2935. https://doi.org/10.1038/ncomms3935
  11. Kim, J.W., Gao, P., Liu, Y.C., Semenza, G.L. and Dang, C.V. (2007) Hypoxia-inducible factor 1 and dysregulated c-Myc cooperatively induce vascular endothelial growth factor and metabolic switches hexokinase 2 and pyruvate dehydrogenase kinase 1. Mol. Cell Biol., 27, 7381-7393. https://doi.org/10.1128/MCB.00440-07
  12. Kim, J.W., Zeller, K.I., Wang, Y., Jegga, A.G., Aronow, B.J., O'Donnell, K.A. and Dang, C.V. (2004) Evaluation of myc E-box phylogenetic footprints in glycolytic genes by chromatin immunoprecipitation assays. Mol. Cell Biol., 24, 5923-5936. https://doi.org/10.1128/MCB.24.13.5923-5936.2004
  13. Bensaad, K., Tsuruta, A., Selak, M.A., Vidal, M.N., Nakano, K., Bartrons, R., Gottlieb, E. and Vousden, K.H. (2006) TIGAR, a p53-inducible regulator of glycolysis and apoptosis. Cell, 126, 107-120. https://doi.org/10.1016/j.cell.2006.05.036
  14. Mikawa, T., Maruyama, T., Okamoto, K., Nakagama, H., Lleonart, M.E., Tsusaka, T., Hori, K., Murakami, I., Izumi, T., Takaori-Kondo, A., Yokode, M., Peters, G., Beach, D. and Kondoh, H. (2014) Senescence-inducing stress promotes proteolysis of phosphoglycerate mutase via ubiquitin ligase Mdm2. J. Cell Biol., 204, 729-745. https://doi.org/10.1083/jcb.201306149
  15. Christofk, H.R., Vander Heiden, M.G., Harris, M.H., Ramanathan, A., Gerszten, R.E., Wei, R., Fleming, M.D., Schreiber, S.L. and Cantley, L.C. (2008) The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature, 452, 230-233. https://doi.org/10.1038/nature06734
  16. Zhan, C., Yan, L., Wang, L., Ma, J., Jiang, W., Zhang, Y., Shi, Y. and Wang, Q. (2015) Isoform switch of pyruvate kinase M1 indeed occurs but not to pyruvate kinase M2 in human tumorigenesis. PLoS One, 10, e0118663. https://doi.org/10.1371/journal.pone.0118663
  17. Taniguchi, K., Ito, Y., Sugito, N., Kumazaki, M., Shinohara, H., Yamada, N., Nakagawa, Y., Sugiyama, T., Futamura, M., Otsuki, Y., Yoshida, K., Uchiyama, K. and Akao, Y. (2015) Organ-specific PTB1-associated microRNAs determine expression of pyruvate kinase isoforms. Sci. Rep., 5, 8647. https://doi.org/10.1038/srep08647
  18. David, C.J., Chen, M., Assanah, M., Canoll, P. and Manley, J.L. (2010) HnRNP proteins controlled by c-Myc deregulate pyruvate kinase mRNA splicing in cancer. Nature, 463, 364-368. https://doi.org/10.1038/nature08697
  19. Desai, S., Ding, M., Wang, B., Lu, Z., Zhao, Q., Shaw, K., Yung, W.K., Weinstein, J.N., Tan, M. and Yao, J. (2014) Tissue- specific isoform switch and DNA hypomethylation of the pyruvate kinase PKM gene in human cancers. Oncotarget, 5, 8202-8210. https://doi.org/10.18632/oncotarget.1159
  20. Xu, X., Li, J., Sun, X., Guo, Y., Chu, D., Wei, L., Li, X., Yang, G., Liu, X., Yao, L., Zhang, J. and Shen, L. (2015) Tumor suppressor NDRG2 inhibits glycolysis and glutaminolysis in colorectal cancer cells by repressing c-Myc expression. Oncotarget, 6, 26161-26176. https://doi.org/10.18632/oncotarget.4544
  21. Draoui, N. and Feron, O. (2011) Lactate shuttles at a glance: from physiological paradigms to anti-cancer treatments. Dis. Models Mech., 4, 727-732. https://doi.org/10.1242/dmm.007724
  22. Doherty, J.R., Yang, C., Scott, K.E., Cameron, M.D., Fallahi, M., Li, W., Hall, M.A., Amelio, A.L., Mishra, J.K., Li, F., Tortosa, M., Genau, H.M., Rounbehler, R.J., Lu, Y., Dang, C.V., Kumar, K.G., Butler, A.A., Bannister, T.D., Hooper, A.T., Unsal-Kacmaz, K., Roush, W.R. and Cleveland, J.L. (2014) Blocking lactate export by inhibiting the Myc target MCT1 Disables glycolysis and glutathione synthesis. Cancer Res., 74, 908-920. https://doi.org/10.1158/0008-5472.CAN-13-2034
  23. Herzig, S., Raemy, E., Montessuit, S., Veuthey, J.L., Zamboni, N., Westermann, B., Kunji, E.R. and Martinou, J.C. (2012) Identification and functional expression of the mitochondrial pyruvate carrier. Science, 337, 93-96. https://doi.org/10.1126/science.1218530
  24. Bricker, D.K., Taylor, E.B., Schell, J.C., Orsak, T., Boutron, A., Chen, Y.C., Cox, J.E., Cardon, C.M., Van Vranken, J.G., Dephoure, N., Redin, C., Boudina, S., Gygi, S.P., Brivet, M., Thummel, C.S. and Rutter, J. (2012) A mitochondrial pyruvate carrier required for pyruvate uptake in yeast, Drosophila, and humans. Science, 337, 96-100. https://doi.org/10.1126/science.1218099
  25. Schell, J.C., Olson, K.A., Jiang, L., Hawkins, A.J., Van Vranken, J.G., Xie, J., Egnatchik, R.A., Earl, E.G., DeBerardinis, R.J. and Rutter, J. (2014) A role for the mitochondrial pyruvate carrier as a repressor of the Warburg effect and colon cancer cell growth. Mol. Cell, 56, 400-413. https://doi.org/10.1016/j.molcel.2014.09.026
  26. Sun, X.R., Sun, Z., Zhu, Z., Guan, H.X., Li, C.Y., Zhang, J.Y., Zhang, Y.N., Zhou, H., Zhang, H.J., Xu, H.M. and Sun, M.J. (2015) Expression of pyruvate dehydrogenase is an independent prognostic marker in gastric cancer. World J. Gastroenterol., 21, 5336-5344. https://doi.org/10.3748/wjg.v21.i17.5336
  27. Hur, H., Xuan, Y., Kim, Y.B., Lee, G., Shim, W., Yun, J., Ham, I.H. and Han, S.U. (2013) Expression of pyruvate dehydrogenase kinase-1 in gastric cancer as a potential therapeutic target. Int. J. Oncol., 42, 44-54. https://doi.org/10.3892/ijo.2012.1687
  28. Sellers, K., Fox, M.P., Bousamra, M. 2nd, Slone, S.P., Higashi, R.M., Miller, D.M., Wang, Y., Yan, J., Yuneva, M.O., Deshpande, R., Lane, A.N. and Fan, T.W. (2015) Pyruvate carboxylase is critical for non-small-cell lung cancer proliferation. J. Clin. Invest., 125, 687-698. https://doi.org/10.1172/JCI72873
  29. Cardaci, S., Zheng, L., MacKay, G., van den Broek, N.J., MacKenzie, E.D., Nixon, C., Stevenson, D., Tumanov, S., Bulusu, V., Kamphorst, J.J., Vazquez, A., Fleming, S., Schiavi, F., Kalna, G., Blyth, K., Strathdee, D. and Gottlieb, E. (2015) Pyruvate carboxylation enables growth of SDH-deficient cells by supporting aspartate biosynthesis. Nat. Cell Biol., 17, 1317-1326. https://doi.org/10.1038/ncb3233
  30. Wutthisathapornchai, A., Vongpipatana, T., Muangsawat, S., Boonsaen, T., MacDonald, M.J. and Jitrapakdee, S. (2014) Multiple E-boxes in the distal promoter of the rat pyruvate carboxylase gene function as a glucose-responsive element. PLoS One, 9, e102730. https://doi.org/10.1371/journal.pone.0102730
  31. Mates, J.M., Segura, J.A., Campos-Sandoval, J.A., Lobo, C., Alonso, L., Alonso, F.J. and Marquez, J. (2009) Glutamine homeostasis and mitochondrial dynamics. Int. J. Biochem. Cell Biol., 41, 2051-2061. https://doi.org/10.1016/j.biocel.2009.03.003
  32. Cetindis, M., Biegner, T., Munz, A., Teriete, P., Reinert, S. and Grimm, M. (2015) Glutaminolysis and carcinogenesis of oral squamous cell carcinoma. Eur. Arch. Otorhinolaryngol., 1-9. doi:10.1007/s00405-015-3543-7.
  33. Ren, P., Yue, M., Xiao, D., Xiu, R., Gan, L., Liu, H. and Qing, G. (2015) ATF4 and N-Myc coordinate glutamine metabolism in MYCN-amplified neuroblastoma cells through ASCT2 activation. J. Pathol., 235, 90-100. https://doi.org/10.1002/path.4429
  34. Gao, P., Tchernyshyov, I., Chang, T.C., Lee, Y.S., Kita, K., Ochi, T., Zeller, K.I., De Marzo, A.M., Van Eyk, J.E., Mendell, J.T. and Dang, C.V. (2009) c-Myc suppression of miR- 23a/b enhances mitochondrial glutaminase expression and glutamine metabolism. Nature, 458, 762-765. https://doi.org/10.1038/nature07823
  35. DeBerardinis, R.J., Mancuso, A., Daikhin, E., Nissim, I., Yudkoff, M., Wehrli, S. and Thompson, C.B. (2007) Beyond aerobic glycolysis: transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis. Proc. Natl. Acad. Sci. U.S.A., 104, 19345-19350. https://doi.org/10.1073/pnas.0709747104
  36. Meng, M., Chen, S., Lao, T., Liang, D. and Sang, N. (2010) Nitrogen anabolism underlies the importance of glutaminolysis in proliferating cells. Cell Cycle, 9, 3921-3932. https://doi.org/10.4161/cc.9.19.13139
  37. Hunnewell, M.G. and Forbes, N.S. (2010) Active and inactive metabolic pathways in tumor spheroids: determination by GCMS. Biotechnol. Prog., 26, 789-796.
  38. Yoo, H., Stephanopoulos, G. and Kelleher, J.K. (2004) Quantifying carbon sources for de novo lipogenesis in wild-type and IRS-1 knockout brown adipocytes. J. Lipid Res., 45, 1324-1332. https://doi.org/10.1194/jlr.M400031-JLR200
  39. Parlo, R.A. and Coleman, P.S. (1984) Enhanced rate of citrate export from cholesterol-rich hepatoma mitochondria. The truncated Krebs cycle and other metabolic ramifications of mitochondrial membrane cholesterol. J. Biol. Chem., 259, 9997-10003.
  40. Metallo, C.M., Gameiro, P.A., Bell, E.L., Mattaini, K.R., Yang, J., Hiller, K., Jewell, C.M., Johnson, Z.R., Irvine, D.J., Guarente, L., Kelleher, J.K., Vander Heiden, M.G., Iliopoulos, O. and Stephanopoulos, G. (2011) Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia. Nature, 481, 380-384.
  41. Wise, D.R., Ward, P.S., Shay, J.E., Cross, J.R., Gruber, J.J., Sachdeva, U.M., Platt, J.M., DeMatteo, R.G., Simon, M.C. and Thompson, C.B. (2011) Hypoxia promotes isocitrate dehydrogenase-dependent carboxylation of alpha-ketoglutarate to citrate to support cell growth and viability. Proc. Natl. Acad. Sci. U.S.A., 108, 19611-19616. https://doi.org/10.1073/pnas.1117773108
  42. Mullen, A.R., Wheaton, W.W., Jin, E.S., Chen, P.H., Sullivan, L.B., Cheng, T., Yang, Y., Linehan, W.M., Chandel, N.S. and DeBerardinis, R.J. (2011) Reductive carboxylation supports growth in tumour cells with defective mitochondria. Nature, 481, 385-388.
  43. Rehberg, M., Rath, A., Ritter, J.B., Genzel, Y. and Reichl, U. (2014) Changes in intracellular metabolite pools during growth of adherent MDCK cells in two different media. Appl. Microbiol. Biotechnol., 98, 385-397. https://doi.org/10.1007/s00253-013-5329-4
  44. Levine, A.J. and Puzio-Kuter, A.M. (2010) The control of the metabolic switch in cancers by oncogenes and tumor suppressor genes. Science, 330, 1340-1344. https://doi.org/10.1126/science.1193494
  45. Leite, T.C., Coelho, R.G., Da Silva, D., Coelho, W.S., Marinho-Carvalho, M.M. and Sola-Penna, M. (2011) Lactate downregulates the glycolytic enzymes hexokinase and phosphofructokinase in diverse tissues from mice. FEBS Lett., 585, 92-98. https://doi.org/10.1016/j.febslet.2010.11.009
  46. Vander Heiden, M.G., Locasale, J.W., Swanson, K.D., Sharfi, H., Heffron, G.J., Amador-Noguez, D., Christofk, H.R., Wagner, G., Rabinowitz, J.D., Asara, J.M. and Cantley, L.C. (2010) Evidence for an alternative glycolytic pathway in rapidly proliferating cells. Science, 329, 1492-1499. https://doi.org/10.1126/science.1188015
  47. Yang, W. and Lu, Z. (2015) Pyruvate kinase M2 at a glance. J. Cell Sci., 128, 1655-1660. https://doi.org/10.1242/jcs.166629
  48. Hosios, A.M., Fiske, B.P., Gui, D.Y. and Vander Heiden, M.G. (2015) Lack of evidence for PKM2 protein kinase activity. Mol. Cell, 59, 850-857. https://doi.org/10.1016/j.molcel.2015.07.013
  49. Cairns, R.A., Harris, I.S. and Mak, T.W. (2011) Regulation of cancer cell metabolism. Nat. Rev. Cancer, 11, 85-95. https://doi.org/10.1038/nrc2981
  50. Vander Heiden, M.G., Cantley, L.C. and Thompson, C.B. (2009) Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science, 324, 1029-1033. https://doi.org/10.1126/science.1160809
  51. Hitosugi, T., Zhou, L., Elf, S., Fan, J., Kang, H.B., Seo, J.H., Shan, C., Dai, Q., Zhang, L., Xie, J., Gu, T.L., Jin, P., Alečkovic, M., LeRoy, G., Kang, Y., Sudderth, J.A., DeBerardinis, R.J., Luan, C.H., Chen, G.Z., Muller, S., Shin, D.M., Owonikoko, T.K., Lonial, S., Arellano, M.L., Khoury, H.J., Khuri, F.R., Lee, B.H., Ye, K., Boggon, T.J., Kang, S., He, C. and Chen, J. (2012) Phosphoglycerate mutase 1 coordinates glycolysis and biosynthesis to promote tumor growth. Cancer Cell, 22, 585-600. https://doi.org/10.1016/j.ccr.2012.09.020
  52. Jiang, X., Sun, Q., Li, H., Li, K. and Ren, X. (2014) The role of phosphoglycerate mutase 1 in tumor aerobic glycolysis and its potential therapeutic implications. Int. J. Cancer, 135, 1991-1996. https://doi.org/10.1002/ijc.28637
  53. Stine, Z.E. and Dang, C.V. (2013) Stress eating and tuning out: cancer cells re-wire metabolism to counter stress. Crit. Rev. Biochem. Mol. Biol., 48, 609-619. https://doi.org/10.3109/10409238.2013.844093
  54. Hirayama, A., Kami, K., Sugimoto, M., Sugawara, M., Toki, N., Onozuka, H., Kinoshita, T., Saito, N., Ochiai, A., Tomita, M., Esumi, H. and Soga, T. (2009) Quantitative metabolome profiling of colon and stomach cancer microenvironment by capillary electrophoresis time-of-flight mass spectrometry. Cancer Res., 69, 4918-4925. https://doi.org/10.1158/0008-5472.CAN-08-4806
  55. Berg, J., Tymoczko, J. and Stryer, L. (2002) Entry to the Citric Acid Cycle and Metabolism Through It Are Controlled in Biochemistry Ed. New York.
  56. Fang, M., Shen, Z., Huang, S., Zhao, L., Chen, S., Mak, T.W. and Wang, X. (2010) The ER UDPase ENTPD5 promotes protein N-glycosylation, the Warburg effect, and proliferation in the PTEN pathway. Cell, 143, 711-724. https://doi.org/10.1016/j.cell.2010.10.010
  57. Shirato, K., Nakajima, K., Korekane, H., Takamatsu, S., Gao, C., Angata, T., Ohtsubo, K. and Taniguchi, N. (2011) Hypoxic regulation of glycosylation via the N-acetylglucosamine cycle. J. Clin. Biochem. Nutr., 48, 20-25.
  58. Israelsen, W.J. and Vander Heiden, M.G. (2010) ATP consumption promotes cancer metabolism. Cell, 143, 669-671. https://doi.org/10.1016/j.cell.2010.11.010
  59. Berg, J., Tymoczko, J. and Stryer, L. (2002) Oxidative Phosphorylation in Biochemistry Ed. New York.
  60. Bagkos, G., Koufopoulos, K. and Piperi, C. (2015) Mitochondrial emitted electromagnetic signals mediate retrograde signaling. Med. Hypotheses, 85, 810-818. https://doi.org/10.1016/j.mehy.2015.10.004
  61. Sullivan, L.B., Gui, D.Y., Hosios, A.M., Bush, L.N., Freinkman, E. and Vander Heiden, M.G. (2015) Supporting aspartate biosynthesis is an essential function of respiration in proliferating cells. Cell, 162, 552-563. https://doi.org/10.1016/j.cell.2015.07.017
  62. Birsoy, K., Wang, T., Chen, W.W., Freinkman, E., Abu- Remaileh, M. and Sabatini, D.M. (2015) An essential role of the mitochondrial electron transport chain in cell proliferation is to enable aspartate synthesis. Cell, 162, 540-551. https://doi.org/10.1016/j.cell.2015.07.016
  63. Krebs, H.A. and Johnson, W.A. (1937) Metabolism of ketonic acids in animal tissues. Biochem. J., 31, 645-660. https://doi.org/10.1042/bj0310645
  64. Pagliarini, D.J. and Rutter, J. (2013) Hallmarks of a new era in mitochondrial biochemistry. Genes Dev., 27, 2615-2627. https://doi.org/10.1101/gad.229724.113

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