Mitochondria as biosynthetic factories for cancer proliferation

详细信息    查看全文

• 作者：Christopher S Ahn (1)
  Christian M Metallo (1) (2)
  
  1. Department of Bioengineering ; University of California ; San Diego ; La Jolla ; CA ; 92093 ; USA
  2. Moores Cancer Center ; University of California ; San Diego ; La Jolla ; CA ; 92093 ; USA
  
• 关键词：Cancer ; Mitochondria ; Biosynthesis ; Amino acids ; Nucleotides ; Anaplerosis ; Lipogenesis
• 刊名：Cancer & Metabolism
• 出版年：2015
• 出版时间：December 2015
• 年：2015
• 卷：3
• 期：1
• 全文大小：845 KB
• 参考文献：1. Warburg O. On the origin of cancer cells. Science. 1956;123:309鈥?4. 3.3191.309" target="_blank" title="It opens in new window">CrossRef
  2. Farwell MD, Pryma DA, Mankoff DA. PET/CT imaging in cancer: current applications and future directions. Cancer. 2014;120:3433鈥?5. CrossRef
  3. Maher EA, Marin-Valencia I, Bachoo RM, Mashimo T, Raisanen J, Hatanpaa KJ, et al. Metabolism of [U-13 C]glucose in human brain tumors in vivo. NMR Biomed. 2012;25:1234鈥?4. CrossRef
  4. Richardson AD, Yang C, Osterman A, Smith JW. Central carbon metabolism in the progression of mammary carcinoma. Breast Cancer Res Treat. 2008;110:297鈥?07. 32-3" target="_blank" title="It opens in new window">CrossRef
  5. Lane AN, Fan TW, Bousamra 2nd M, Higashi RM, Yan J, Miller DM. Stable isotope-resolved metabolomics (SIRM) in cancer research with clinical application to nonsmall cell lung cancer. OMICS. 2011;15:173鈥?2. CrossRef
  6. Cheng T, Sudderth J, Yang C, Mullen AR, Jin ES, Mates JM, et al. Pyruvate carboxylase is required for glutamine-independent growth of tumor cells. Proc Natl Acad Sci U S A. 2011;108:8674鈥?. 3/pnas.1016627108" target="_blank" title="It opens in new window">CrossRef
  7. Marin-Valencia I, Yang C, Mashimo T, Cho S, Baek H, Yang XL, et al. Analysis of tumor metabolism reveals mitochondrial glucose oxidation in genetically diverse human glioblastomas in the mouse brain in vivo. Cell Metab. 2012;15:827鈥?7. CrossRef
  8. Kamphorst JJ, Cross JR, Fan J, de Stanchina E, Mathew R, White EP, et al. Hypoxic and Ras-transformed cells support growth by scavenging unsaturated fatty acids from lysophospholipids. Proc Natl Acad Sci U S A. 2013;110:8882鈥?. 3/pnas.1307237110" target="_blank" title="It opens in new window">CrossRef
  9. Metallo CM, Gameiro PA, Bell EL, Mattaini KR, Yang J, Hiller K, et al. Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia. Nature. 2012;481:380鈥?.
  10. Hatzivassiliou G, Zhao F, Bauer DE, Andreadis C, Shaw AN, Dhanak D, et al. ATP citrate lyase inhibition can suppress tumor cell growth. Cancer Cell. 2005;8:311鈥?1. CrossRef
  11. Gaglio D, Metallo CM, Gameiro PA, Hiller K, Danna LS, Balestrieri C, et al. Oncogenic K-Ras decouples glucose and glutamine metabolism to support cancer cell growth. Mol Syst Biol. 2011;7:523. 38/msb.2011.56" target="_blank" title="It opens in new window">CrossRef
  12. Vizan P, Boros LG, Figueras A, Capella G, Mangues R, Bassilian S, et al. K-ras codon-specific mutations produce distinctive metabolic phenotypes in NIH3T3 mice [corrected] fibroblasts. Cancer Res. 2005;65:5512鈥?. CrossRef
  13. Bauer DE, Hatzivassiliou G, Zhao F, Andreadis C, Thompson CB. ATP citrate lyase is an important component of cell growth and transformation. Oncogene. 2005;24:6314鈥?2. 38/sj.onc.1208773" target="_blank" title="It opens in new window">CrossRef
  14. Porstmann T, Santos CR, Griffiths B, Cully M, Wu M, Leevers S, et al. SREBP activity is regulated by mTORC1 and contributes to Akt-dependent cell growth. Cell Metab. 2008;8:224鈥?6. CrossRef
  15. Griffiths B, Lewis CA, Bensaad K, Ros S, Zhang Q, Ferber EC, et al. Sterol regulatory element binding protein-dependent regulation of lipid synthesis supports cell survival and tumor growth. Cancer Metab. 2013;1:3. 3002-1-3" target="_blank" title="It opens in new window">CrossRef
  16. Williams KJ, Argus JP, Zhu Y, Wilks MQ, Marbois BN, York AG, et al. An essential requirement for the SCAP/SREBP signaling axis to protect cancer cells from lipotoxicity. Cancer Res. 2013;73:2850鈥?2. 3-0382-T" target="_blank" title="It opens in new window">CrossRef
  17. Csibi A, Fendt SM, Li C, Poulogiannis G, Choo AY, Chapski DJ, et al. The mTORC1 pathway stimulates glutamine metabolism and cell proliferation by repressing SIRT4. Cell. 2013;153:840鈥?4. 3.04.023" target="_blank" title="It opens in new window">CrossRef
  18. Duvel K, Yecies JL, Menon S, Raman P, Lipovsky AI, Souza AL, et al. Activation of a metabolic gene regulatory network downstream of mTOR complex 1. Mol Cell. 2010;39:171鈥?3. CrossRef
  19. Grassian AR, Metallo CM, Coloff JL, Stephanopoulos G, Brugge JS. Erk regulation of pyruvate dehydrogenase flux through PDK4 modulates cell proliferation. Genes Dev. 2011;25:1716鈥?3. CrossRef
  20. Kim JW, Tchernyshyov I, Semenza GL, Dang CV. HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab. 2006;3:177鈥?5. CrossRef
  21. Papandreou I, Cairns RA, Fontana L, Lim AL, Denko NC. HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption. Cell Metab. 2006;3:187鈥?7. CrossRef
  22. Semenza GL. HIF-1: upstream and downstream of cancer metabolism. Curr Opin Genet Dev. 2010;20:51鈥?. CrossRef
  23. Bonnet S, Archer SL, Allalunis-Turner J, Haromy A, Beaulieu C, Thompson R, et al. A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth. Cancer Cell. 2007;11:37鈥?1. CrossRef
  24. Gameiro PA, Yang J, Metelo AM, Perez-Carro R, Baker R, Wang Z, et al. In vivo HIF-mediated reductive carboxylation is regulated by citrate levels and sensitizes VHL-deficient cells to glutamine deprivation. Cell Metab. 2013;17:372鈥?5. 3.02.002" target="_blank" title="It opens in new window">CrossRef
  25. Wise DR, Ward PS, Shay JE, Cross JR, Gruber JJ, Sachdeva UM, et al. Hypoxia promotes isocitrate dehydrogenase-dependent carboxylation of alpha-ketoglutarate to citrate to support cell growth and viability. Proc Natl Acad Sci U S A. 2011;108:19611鈥?. 3/pnas.1117773108" target="_blank" title="It opens in new window">CrossRef
  26. Zimmer M, Doucette D, Siddiqui N, Iliopoulos O. Inhibition of hypoxia-inducible factor is sufficient for growth suppression of VHL鈭?鈭?tumors. Mol Cancer Res. 2004;2:89鈥?5.
  27. Kaplon J, Zheng L, Meissl K, Chaneton B, Selivanov VA, Mackay G, et al. A key role for mitochondrial gatekeeper pyruvate dehydrogenase in oncogene-induced senescence. Nature. 2013;498:109鈥?2. 38/nature12154" target="_blank" title="It opens in new window">CrossRef
  28. Schell JC, Olson KA, Jiang L, Hawkins AJ, Van Vranken JG, Xie J, et al. A role for the mitochondrial pyruvate carrier as a repressor of the Warburg effect and colon cancer cell growth. Mol Cell. 2014;56:400鈥?3. CrossRef
  29. Vacanti NM, Divakaruni AS, Green CR, Parker SJ, Henry RR, Ciaraldi TP, et al. Regulation of substrate utilization by the mitochondrial pyruvate carrier. Mol Cell. 2014;56:425鈥?5. CrossRef
  30. Yang C, Ko B, Hensley CT, Jiang L, Wasti AT, Kim J, et al. Glutamine oxidation maintains the TCA cycle and cell survival during impaired mitochondrial pyruvate transport. Mol Cell. 2014;56:414鈥?4. CrossRef
  31. Comerford SA, Huang Z, Du X, Wang Y, Cai L, Witkiewicz AK, et al. Acetate dependence of tumors. Cell. 2014;159:1591鈥?02. CrossRef
  32. Mashimo T, Pichumani K, Vemireddy V, Hatanpaa KJ, Singh DK, Sirasanagandla S, et al. Acetate is a bioenergetic substrate for human glioblastoma and brain metastases. Cell. 2014;159:1603鈥?4. CrossRef
  33. Young RM, Ackerman D, Quinn ZL, Mancuso A, Gruber M, Liu L, et al. Dysregulated mTORC1 renders cells critically dependent on desaturated lipids for survival under tumor-like stress. Genes Dev. 2013;27:1115鈥?1. 30.112" target="_blank" title="It opens in new window">CrossRef
  34. Commisso C, Davidson SM, Soydaner-Azeloglu RG, Parker SJ, Kamphorst JJ, Hackett S, et al. Macropinocytosis of protein is an amino acid supply route in Ras-transformed cells. Nature. 2013;497:633鈥?. 38/nature12138" target="_blank" title="It opens in new window">CrossRef
  35. Weinberg F, Hamanaka R, Wheaton WW, Weinberg S, Joseph J, Lopez M, et al. Mitochondrial metabolism and ROS generation are essential for Kras-mediated tumorigenicity. Proc Natl Acad Sci U S A. 2010;107:8788鈥?3. 3/pnas.1003428107" target="_blank" title="It opens in new window">CrossRef
  36. Yang C, Sudderth J, Dang T, Bachoo RM, McDonald JG, DeBerardinis RJ. Glioblastoma cells require glutamate dehydrogenase to survive impairments of glucose metabolism or Akt signaling. Cancer Res. 2009;69:7986鈥?3. CrossRef
  37. Gao P, Tchernyshyov I, Chang TC, Lee YS, Kita K, Ochi T, et al. c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism. Nature. 2009;458:762鈥?. 38/nature07823" target="_blank" title="It opens in new window">CrossRef
  38. Le A, Lane AN, Hamaker M, Bose S, Gouw A, Barbi J, et al. Glucose-independent glutamine metabolism via TCA cycling for proliferation and survival in B cells. Cell Metab. 2012;15:110鈥?1. CrossRef
  39. Seltzer MJ, Bennett BD, Joshi AD, Gao P, Thomas AG, Ferraris DV, et al. Inhibition of glutaminase preferentially slows growth of glioma cells with mutant IDH1. Cancer Res. 2010;70:8981鈥?. CrossRef
  40. Wang JB, Erickson JW, Fuji R, Ramachandran S, Gao P, Dinavahi R, et al. Targeting mitochondrial glutaminase activity inhibits oncogenic transformation. Cancer Cell. 2010;18:207鈥?9. CrossRef
  41. Liu W, Le A, Hancock C, Lane AN, Dang CV, Fan TW, et al. Reprogramming of proline and glutamine metabolism contributes to the proliferative and metabolic responses regulated by oncogenic transcription factor c-MYC. Proc Natl Acad Sci U S A. 2012;109:8983鈥?. 3/pnas.1203244109" target="_blank" title="It opens in new window">CrossRef
  42. Scott DA, Richardson AD, Filipp FV, Knutzen CA, Chiang GG, Ronai ZA, et al. Comparative metabolic flux profiling of melanoma cell lines: beyond the Warburg effect. J Biol Chem. 2011;286:42626鈥?4. CrossRef
  43. Son J, Lyssiotis CA, Ying H, Wang X, Hua S, Ligorio M, et al. Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway. Nature. 2013;496:101鈥?. 38/nature12040" target="_blank" title="It opens in new window">CrossRef
  44. DeBerardinis RJ, Mancuso A, Daikhin E, Nissim I, Yudkoff M, Wehrli S, et al. 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. 2007;104:19345鈥?0. 3/pnas.0709747104" target="_blank" title="It opens in new window">CrossRef
  45. Grassian AR, Parker SJ, Davidson SM, Divakaruni AS, Green CR, Zhang X, et al. IDH1 mutations alter citric acid cycle metabolism and increase dependence on oxidative mitochondrial metabolism. Cancer Res. 2014;74:3317鈥?1. CrossRef
  46. Diehn M, Cho RW, Lobo NA, Kalisky T, Dorie MJ, Kulp AN, et al. Association of reactive oxygen species levels and radioresistance in cancer stem cells. Nature. 2009;458:780鈥?. 38/nature07733" target="_blank" title="It opens in new window">CrossRef
  47. Jiang P, Du W, Mancuso A, Wellen KE, Yang X. Reciprocal regulation of p53 and malic enzymes modulates metabolism and senescence. Nature. 2013;493:689鈥?3. 38/nature11776" target="_blank" title="It opens in new window">CrossRef
  48. Mullen AR, Wheaton WW, Jin ES, Chen PH, Sullivan LB, Cheng T, et al. Reductive carboxylation supports growth in tumour cells with defective mitochondria. Nature. 2012;481:385鈥?.
  49. Fendt SM, Bell EL, Keibler MA, Olenchock BA, Mayers JR, Wasylenko TM, et al. Reductive glutamine metabolism is a function of the alpha-ketoglutarate to citrate ratio in cells. Nat Commun. 2013;4:2236. 38/ncomms3236" target="_blank" title="It opens in new window">CrossRef
  50. Gameiro PA, Laviolette LA, Kelleher JK, Iliopoulos O, Stephanopoulos G. Cofactor balance by nicotinamide nucleotide transhydrogenase (NNT) coordinates reductive carboxylation and glucose catabolism in the tricarboxylic acid (TCA) cycle. J Biol Chem. 2013;288:12967鈥?7. 396796" target="_blank" title="It opens in new window">CrossRef
  51. Fan J, Kamphorst JJ, Mathew R, Chung MK, White E, Shlomi T, et al. Glutamine-driven oxidative phosphorylation is a major ATP source in transformed mammalian cells in both normoxia and hypoxia. Mol Syst Biol. 2013;9:712. 38/msb.2013.65" target="_blank" title="It opens in new window">CrossRef
  52. Kung HN, Marks JR, Chi JT. Glutamine synthetase is a genetic determinant of cell type-specific glutamine independence in breast epithelia. PLoS Genet. 2011;7:e1002229. 371/journal.pgen.1002229" target="_blank" title="It opens in new window">CrossRef
  53. De Ingeniis J, Ratnikov B, Richardson AD, Scott DA, Aza-Blanc P, De SK, et al. Functional specialization in proline biosynthesis of melanoma. PLoS One. 2012;7:e45190. 371/journal.pone.0045190" target="_blank" title="It opens in new window">CrossRef
  54. Nilsson R, Jain M, Madhusudhan N, Sheppard NG, Strittmatter L, Kampf C, et al. Metabolic enzyme expression highlights a key role for MTHFD2 and the mitochondrial folate pathway in cancer. Nat Commun. 2014;5:3128.
  55. Hagedorn CH, Phang JM. Transfer of reducing equivalents into mitochondria by the interconversions of proline and delta 1-pyrroline-5-carboxylate. Arch Biochem Biophys. 1983;225:95鈥?01. 3-9861(83)90010-3" target="_blank" title="It opens in new window">CrossRef
  56. Liu Y, Borchert GL, Donald SP, Diwan BA, Anver M, Phang JM. Proline oxidase functions as a mitochondrial tumor suppressor in human cancers. Cancer Res. 2009;69:6414鈥?2. 3" target="_blank" title="It opens in new window">CrossRef
  57. Liu W, Zabirnyk O, Wang H, Shiao YH, Nickerson ML, Khalil S, et al. miR-23b targets proline oxidase, a novel tumor suppressor protein in renal cancer. Oncogene. 2010;29:4914鈥?4. 38/onc.2010.237" target="_blank" title="It opens in new window">CrossRef
  58. Ying H, Kimmelman AC, Lyssiotis CA, Hua S, Chu GC, Fletcher-Sananikone E, et al. Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism. Cell. 2012;149:656鈥?0. CrossRef
  59. Viale A, Pettazzoni P, Lyssiotis CA, Ying H, Sanchez N, Marchesini M, et al. Oncogene ablation-resistant pancreatic cancer cells depend on mitochondrial function. Nature. 2014;514:628鈥?2. 38/nature13611" target="_blank" title="It opens in new window">CrossRef
  60. Zhang J, Fan J, Venneti S, Cross JR, Takagi T, Bhinder B, et al. Asparagine plays a critical role in regulating cellular adaptation to glutamine depletion. Mol Cell. 2014;56:205鈥?8. CrossRef
  61. Gutierrez JA, Pan YX, Koroniak L, Hiratake J, Kilberg MS, Richards NG. An inhibitor of human asparagine synthetase suppresses proliferation of an L-asparaginase-resistant leukemia cell line. Chem Biol. 2006;13:1339鈥?7. CrossRef
  62. Richards NG, Kilberg MS. Asparagine synthetase chemotherapy. Annu Rev Biochem. 2006;75:629鈥?4. 3004.142520" target="_blank" title="It opens in new window">CrossRef
  63. Filipp FV, Ratnikov B, De Ingeniis J, Smith JW, Osterman AL, Scott DA. Glutamine-fueled mitochondrial metabolism is decoupled from glycolysis in melanoma. Pigment Cell Melanoma Res. 2012;25:732鈥?. CrossRef
  64. Holm E, Hagmuller E, Staedt U, Schlickeiser G, Gunther HJ, Leweling H, et al. Substrate balances across colonic carcinomas in humans. Cancer Res. 1995;55:1373鈥?.
  65. Hiller K, Metallo CM, Kelleher JK, Stephanopoulos G. Nontargeted elucidation of metabolic pathways using stable-isotope tracers and mass spectrometry. Anal Chem. 2010;82:6621鈥?. CrossRef
  66. Tonjes M, Barbus S, Park YJ, Wang W, Schlotter M, Lindroth AM, et al. BCAT1 promotes cell proliferation through amino acid catabolism in gliomas carrying wild-type IDH1. Nat Med. 2013;19:901鈥?. 38/nm.3217" target="_blank" title="It opens in new window">CrossRef
  67. Mullen AR, Hu Z, Shi X, Jiang L, Boroughs LK, Kovacs Z, et al. Oxidation of alpha-ketoglutarate is required for reductive carboxylation in cancer cells with mitochondrial defects. Cell reports. 2014;7:1679鈥?0. 37" target="_blank" title="It opens in new window">CrossRef
  68. He T, Haapa-Paananen S, Kaminskyy VO, Kohonen P, Fey V, Zhivotovsky B, et al. Inhibition of the mitochondrial pyrimidine biosynthesis enzyme dihydroorotate dehydrogenase by doxorubicin and brequinar sensitizes cancer cells to TRAIL-induced apoptosis. Oncogene. 2014;33:3538鈥?9. 38/onc.2013.313" target="_blank" title="It opens in new window">CrossRef
  69. Hu J, Locasale JW, Bielas JH, O鈥橲ullivan J, Sheahan K, Cantley LC, et al. Heterogeneity of tumor-induced gene expression changes in the human metabolic network. Nat Biotechnol. 2013;31:522鈥?. 38/nbt.2530" target="_blank" title="It opens in new window">CrossRef
  70. White RM, Cech J, Ratanasirintrawoot S, Lin CY, Rahl PB, Burke CJ, et al. DHODH modulates transcriptional elongation in the neural crest and melanoma. Nature. 2011;471:518鈥?2. 38/nature09882" target="_blank" title="It opens in new window">CrossRef
  71. Zhai H, Song B, Xu X, Zhu W, Ju J. Inhibition of autophagy and tumor growth in colon cancer by miR-502. Oncogene. 2013;32:1570鈥?. 38/onc.2012.167" target="_blank" title="It opens in new window">CrossRef
  72. Khutornenko AA, Roudko VV, Chernyak BV, Vartapetian AB, Chumakov PM, Evstafieva AG. Pyrimidine biosynthesis links mitochondrial respiration to the p53 pathway. Proc Natl Acad Sci U S A. 2010;107:12828鈥?3. 3/pnas.0910885107" target="_blank" title="It opens in new window">CrossRef
  73. Tibbetts AS, Appling DR. Compartmentalization of mammalian folate-mediated one-carbon metabolism. Annu Rev Nutr. 2010;30:57鈥?1. CrossRef
  74. Lewis CA, Parker SJ, Fiske BP, McCloskey D, Gui DY, Green CR, et al. Tracing compartmentalized NADPH metabolism in the cytosol and mitochondria of mammalian cells. Mol Cell. 2014;55:253鈥?3. CrossRef
  75. Anderson DD, Quintero CM, Stover PJ. Identification of a de novo thymidylate biosynthesis pathway in mammalian mitochondria. Proc Natl Acad Sci U S A. 2011;108:15163鈥?. 3/pnas.1103623108" target="_blank" title="It opens in new window">CrossRef
  76. Ye J, Fan J, Venneti S, Wan YW, Pawel BR, Zhang J, et al. Serine catabolism regulates mitochondrial redox control during hypoxia. Cancer discovery. 2014;4:1406鈥?7. CrossRef
  77. Fan J, Ye J, Kamphorst JJ, Shlomi T, Thompson CB, Rabinowitz JD. Quantitative flux analysis reveals folate-dependent NADPH production. Nature. 2014;510:298鈥?02. 38/nature13236" target="_blank" title="It opens in new window">CrossRef
  78. Mitsuishi Y, Taguchi K, Kawatani Y, Shibata T, Nukiwa T, Aburatani H, et al. Nrf2 redirects glucose and glutamine into anabolic pathways in metabolic reprogramming. Cancer Cell. 2012;22:66鈥?9. CrossRef
  79. Wahrheit J, Niklas J, Heinzle E. Metabolic control at the cytosol-mitochondria interface in different growth phases of CHO cells. Metab Eng. 2014;23:9鈥?1. CrossRef
  80. Evans JM, Donnelly LA, Emslie-Smith AM, Alessi DR, Morris AD. Metformin and reduced risk of cancer in diabetic patients. BMJ. 2005;330:1304鈥?. 36/bmj.38415.708634.F7" target="_blank" title="It opens in new window">CrossRef
  81. Shackelford DB, Abt E, Gerken L, Vasquez DS, Seki A, Leblanc M, et al. LKB1 inactivation dictates therapeutic response of non-small cell lung cancer to the metabolism drug phenformin. Cancer Cell. 2013;23:143鈥?8. CrossRef
  82. Andrzejewski S, Gravel SP, Pollak M, St-Pierre J. Metformin directly acts on mitochondria to alter cellular bioenergetics. Cancer Metab. 2014;2:12. 3002-2-12" target="_blank" title="It opens in new window">CrossRef
  83. Wheaton WW, Weinberg SE, Hamanaka RB, Soberanes S, Sullivan LB, Anso E, et al. Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis. eLife. 2014;3:e02242. CrossRef
  84. Hiller K, Metallo CM. Profiling metabolic networks to study cancer metabolism. Curr Opin Biotechnol. 2013;24:60鈥?. CrossRef
  
• 刊物主题：Cancer Research; Oncology; Metabolomics; Metabolic Diseases; Imaging / Radiology; Cell Biology;
• 出版者：BioMed Central
• ISSN：2049-3002

文摘

Unchecked growth and proliferation is a hallmark of cancer, and numerous oncogenic mutations reprogram cellular metabolism to fuel these processes. As a central metabolic organelle, mitochondria execute critical biochemical functions for the synthesis of fundamental cellular components, including fatty acids, amino acids, and nucleotides. Despite the extensive interest in the glycolytic phenotype of many cancer cells, tumors contain fully functional mitochondria that support proliferation and survival. Furthermore, tumor cells commonly increase flux through one or more mitochondrial pathways, and pharmacological inhibition of mitochondrial metabolism is emerging as a potential therapeutic strategy in some cancers. Here, we review the biosynthetic roles of mitochondrial metabolism in tumors and highlight specific cancers where these processes are activated.