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Mitochondria in Cancer Energy Metabolism: Culprits or Bystanders?
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  • Journal title : Toxicological Research
  • Volume 31, Issue 4,  2015, pp.323-330
  • Publisher : The Korean Society of Toxicology
  • DOI : 10.5487/TR.2015.31.4.323
 Title & Authors
Mitochondria in Cancer Energy Metabolism: Culprits or Bystanders?
Kim, Aekyong;
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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.
Cancer;Mitochondria;Metabolism;Aerobic glycolysis;Glutaminolysis;Anaplerosis;Cataplerosis;
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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. crossref(new window)

Coller, H.A. (2014) Is cancer a metabolic disease? Am. J. Pathol., 184, 4-17. crossref(new window)

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.

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. crossref(new window)

Crabtree, H.G. (1929) Observations on the carbohydrate metabolism of tumours. Biochem. J., 23, 536-545. crossref(new window)

Weinhouse, S. (1956) On respiratory impairment in cancer cells. Science, 124, 267-269. crossref(new window)

Senyilmaz, D. and Teleman, A.A. (2015) Chicken or the egg: Warburg effect and mitochondrial dysfunction. F1000Prime Rep., 7, 41.

Hanahan, D. and Weinberg, R.A. (2011) Hallmarks of cancer: the next generation. Cell, 144, 646-674. crossref(new window)

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. crossref(new window)

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.

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. crossref(new window)

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. crossref(new window)

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. crossref(new window)

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. crossref(new window)

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. crossref(new window)

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. crossref(new window)

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. crossref(new window)

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. crossref(new window)

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. crossref(new window)

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. crossref(new window)

Draoui, N. and Feron, O. (2011) Lactate shuttles at a glance: from physiological paradigms to anti-cancer treatments. Dis. Models Mech., 4, 727-732. crossref(new window)

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. crossref(new window)

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. crossref(new window)

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. crossref(new window)

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. crossref(new window)

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. crossref(new window)

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.

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. crossref(new window)

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. crossref(new window)

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. crossref(new window)

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. crossref(new window)

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. crossref(new window)

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. crossref(new window)

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. crossref(new window)

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. crossref(new window)

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. crossref(new window)

Hunnewell, M.G. and Forbes, N.S. (2010) Active and inactive metabolic pathways in tumor spheroids: determination by GCMS. Biotechnol. Prog., 26, 789-796.

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. crossref(new window)

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.

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.

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. crossref(new window)

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.

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. crossref(new window)

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. crossref(new window)

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. crossref(new window)

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. crossref(new window)

Yang, W. and Lu, Z. (2015) Pyruvate kinase M2 at a glance. J. Cell Sci., 128, 1655-1660. crossref(new window)

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. crossref(new window)

Cairns, R.A., Harris, I.S. and Mak, T.W. (2011) Regulation of cancer cell metabolism. Nat. Rev. Cancer, 11, 85-95. crossref(new window)

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. crossref(new window)

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. crossref(new window)

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. crossref(new window)

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. crossref(new window)

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. crossref(new window)

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.

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. crossref(new window)

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.

Israelsen, W.J. and Vander Heiden, M.G. (2010) ATP consumption promotes cancer metabolism. Cell, 143, 669-671. crossref(new window)

Berg, J., Tymoczko, J. and Stryer, L. (2002) Oxidative Phosphorylation in Biochemistry Ed. New York.

Bagkos, G., Koufopoulos, K. and Piperi, C. (2015) Mitochondrial emitted electromagnetic signals mediate retrograde signaling. Med. Hypotheses, 85, 810-818. crossref(new window)

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. crossref(new window)

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. crossref(new window)

Krebs, H.A. and Johnson, W.A. (1937) Metabolism of ketonic acids in animal tissues. Biochem. J., 31, 645-660. crossref(new window)

Pagliarini, D.J. and Rutter, J. (2013) Hallmarks of a new era in mitochondrial biochemistry. Genes Dev., 27, 2615-2627. crossref(new window)