Heterogeneity in Cancer Metabolism: New Concepts in an Old Field

Antioxidants and Redox Signaling

Volumn 26, Issue 9, 2017, Pages 462-485

  Gentric, Géraldine ^a   Mieulet, Virginie ^a   Mechta Grigoriou, Fatima ^a  

^a INSTITUT CURIE   (France)

Author keywords

cancer; immunology; metabolism; mitochondria; oxidative stress; ROS

Indexed keywords

CARBON; FATTY ACID; GLUCOSE; GLUCOSE DERIVATIVE; GLUTAMINE; GLYCINE; REACTIVE OXYGEN METABOLITE; SERINE;

ADULT STEM CELL; BIOENERGY; CANCER CELL; CANCER SURVIVAL; CARBON SOURCE; CARCINOGENESIS; CELL FUNCTION; CELL INVASION; CELL METABOLISM; CELL MIGRATION; CELL PROLIFERATION; CELL SURVIVAL; DETOXIFICATION; FIBROBLAST; GLUCOSE UTILIZATION; HUMAN; IMMUNOCOMPETENT CELL; MALIGNANT NEOPLASM; METASTASIS; MITOCHONDRIAL RESPIRATION; NONHUMAN; NUTRIENT AVAILABILITY; OXIDATIVE PHOSPHORYLATION; OXIDATIVE STRESS; POSITRON EMISSION TOMOGRAPHY; PRIORITY JOURNAL; RESPIRATORY CHAIN; REVIEW; SYNTHESIS; TUMOR ASSOCIATED LEUKOCYTE; TUMOR MICROENVIRONMENT; ANIMAL; CELL TRANSFORMATION; ENERGY METABOLISM; GENE EXPRESSION REGULATION; GENETICS; METABOLISM; MITOCHONDRION; NEOPLASMS; PATHOLOGY; PHENOTYPE;

ANIMALS; CELL TRANSFORMATION, NEOPLASTIC; ENERGY METABOLISM; GENE EXPRESSION REGULATION, ENZYMOLOGIC; GENE EXPRESSION REGULATION, NEOPLASTIC; HUMANS; METABOLIC NETWORKS AND PATHWAYS; MITOCHONDRIA; NEOPLASMS; OXIDATIVE STRESS; PHENOTYPE; REACTIVE OXYGEN SPECIES; TUMOR MICROENVIRONMENT;

EID: 85015251797     PISSN: 15230864     EISSN: 15577716     Source Type: Journal    
DOI: 10.1089/ars.2016.6750     Document Type: Review

References (253)

1. Alexeyev M, Shokolenko I, Wilson G, and LeDoux S. The maintenance of mitochondrial DNA integrity-critical analysis and update. Cold Spring Harbor Perspect Biol 5: a012641, 2013
2. Amelio I, Cutruzzola F, Antonov A, Agostini M, and Melino G. Serine and glycine metabolism in cancer. Trends Biochem Sci 39: 191-198, 2014
3. Anderson S, Bankier AT, Barrell BG, de Bruijn MH, Coulson AR, Drouin J, Eperon IC, Nierlich DP, Roe BA, Sanger F, Schreier PH, Smith AJ, Staden R, and Young IG. Sequence and organization of the human mitochondrial genome. Nature 290: 457-465, 1981
4. Antoch G, Saoudi N, Kuehl H, Dahmen G, Mueller SP, Beyer T, Bockisch A, Debatin JF, and Freudenberg LS. Accuracy of whole-body dual-modality fluorine-18-2-fluoro-2-deoxy-D-glucose positron emission tomography and computed tomography (FDG-PET/CT) for tumor staging in solid tumors: comparison with CT and PET. J Clin Oncol 22: 4357-4368, 2004
5. Augsten M, Sjoberg E, Frings O, Vorrink SU, Frijhoff J, Olsson E, Borg A, and Ostman A. Cancer-associated fibroblasts expressing CXCL14 rely upon NOS1-derived nitric oxide signaling for their tumor-supporting properties. Cancer Res 74: 2999-3010, 2014
6. Bao Y, Mukai K, Hishiki T, Kubo A, Ohmura M, Sugiura Y, Matsuura T, Nagahata Y, Hayakawa N, Yamamoto T, Fukuda R, Saya H, Suematsu M, and Minamishima YA. Energy management by enhanced glycolysis in G1-phase in human colon cancer cells in vitro and in vivo. Mol Cancer Res 11: 973-985, 2013
7. Bardos JI and Ashcroft M. Hypoxia-inducible factor-1 and oncogenic signalling. BioEssays 26: 262-269, 2004
8. Batista L, Gruosso T, and Mechta-Grigoriou F. Ovarian cancer emerging subtypes: role of oxidative stress and fibrosis in tumour development and response to treatment. Int J Biochem Cell Biol 45: 1092-1098, 2013
9. Becker T, Bottinger L, and Pfanner N. Mitochondrial protein import: from transport pathways to an integrated network. Trends Biochem Sci 37: 85-91, 2012
10. Berod L, Friedrich C, Nandan A, Freitag J, Hagemann S, Harmrolfs K, Sandouk A, Hesse C, Castro CN, Bahre H, Tschirner SK, Gorinski N, Gohmert M, Mayer CT, Huehn J, Ponimaskin E, Abraham WR, Muller R, Lochner M, and Sparwasser T. De novo fatty acid synthesis controls the fate between regulatory T and T helper 17 cells. Nat Med 20: 1327-1333, 2014
11. Birsoy K, Wang T, Chen WW, Freinkman E, Abu-Remaileh M, and Sabatini DM. An essential role of the mitochondrial electron transport chain in cell proliferation is to enable aspartate synthesis. Cell 162: 540-551, 2015
12. Bissell MJ and Hines WC. Why don?t we get more cancer? A proposed role of the microenvironment in restraining cancer progression. Nat Med 17: 320-329, 2011
13. Biswas SK. Metabolic reprogramming of immune cells in cancer progression. Immunity 43: 435-449, 2015
14. Biswas SK and Mantovani A. Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. Nat Immunol 11: 889-896, 2010
15. Blanchet E, Annicotte JS, Lagarrigue S, Aguilar V, Clape C, Chavey C, Fritz V, Casas F, Apparailly F, Auwerx J, and Fajas L. E2F transcription factor-1 regulates oxidative metabolism. Nat Cell Biol 13: 1146-1152, 2011
16. Bochet L, Lehuede C, Dauvillier S, Wang YY, Dirat B, Laurent V, Dray C, Guiet R, Maridonneau-Parini I, Le Gonidec S, Couderc B, Escourrou G, Valet P, and Muller C. Adipocyte-derived fibroblasts promote tumor progression and contribute to the desmoplastic reaction in breast cancer. Cancer Res 73: 5657-5668, 2013
17. Bonnans C, Chou J, and Werb Z. Remodelling the extracellular matrix in development and disease. Nat Rev Mol Cell Biol 15: 786-801, 2014
18. Bonnet S, Archer SL, Allalunis-Turner J, Haromy A, Beaulieu C, Thompson R, Lee CT, Lopaschuk GD, Puttagunta L, Bonnet S, Harry G, Hashimoto K, Porter CJ, Andrade MA, Thebaud B, and Michelakis ED. A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth. Cancer Cell 11: 37-51, 2007
19. Bordone L and Guarente L. Calorie restriction, SIRT1 and metabolism: understanding longevity. Nat Rev Mol Cell Biol 6: 298-305, 2005
20. Brahimi-Horn MC, Bellot G, and Pouyssegur J. Hypoxia and energetic tumour metabolism. Curr Opin Genet Dev 21: 67-72, 2011
21. Brahimi-Horn MC, Chiche J, and Pouyssegur J. Hypoxia signalling controls metabolic demand. Curr Opin Cell Biol 19: 223-229, 2007
22. Brennen WN, Rosen DM, Wang H, Isaacs JT, and Denmeade SR. Targeting carcinoma-associated fibroblasts within the tumor stroma with a fibroblast activation protein-activated prodrug. J Natl Cancer Inst 104: 1320-1334, 2012
23. Brix J, Rudiger S, Bukau B, Schneider-Mergener J, and Pfanner N. Distribution of binding sequences for the mitochondrial import receptors Tom20, Tom22, and Tom70 in a presequence-carrying preprotein and a non-cleavable preprotein. J Biol Chem 274: 16522-16530, 1999
24. Cairns RA, Harris IS, and Mak TW. Regulation of cancer cell metabolism. Nat Rev Cancer 11: 85-95, 2011
25. Calon A, Tauriello DV, and Batlle E. TGF-beta in CAFmediated tumor growth and metastasis. Semin Cancer Biol 25: 15-22, 2014
26. Cantor JR and Sabatini DM. Cancer cell metabolism: one hallmark, many faces. Cancer Discov 2: 881-898, 2012
27. Caro P, Kishan AU, Norberg E, Stanley IA, Chapuy B, Ficarro SB, Polak K, Tondera D, Gounarides J, Yin H, Zhou F, Green MR, Chen L, Monti S, Marto JA, Shipp MA, and Danial NN. Metabolic signatures uncover distinct targets in molecular subsets of diffuse large B cell lymphoma. Cancer Cell 22: 547-560, 2012
28. Carracedo A, Cantley LC, and Pandolfi PP. Cancer metabolism: fatty acid oxidation in the limelight. Nat Rev Cancer 13: 227-232, 2013
29. Casazza A, Di Conza G, Wenes M, Finisguerra V, Deschoemaeker S, and Mazzone M. Tumor stroma: a complexity dictated by the hypoxic tumor microenvironment. Oncogene 33: 1743-1754, 2014
30. Chang CH, Qiu J, O?Sullivan D, Buck MD, Noguchi T, Curtis JD, Chen Q, Gindin M, Gubin MM, van der Windt GJ, Tonc E, Schreiber RD, Pearce EJ, and Pearce EL. Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell 162: 1229-1241, 2015
31. Chaudhri VK, Salzler GG, Dick SA, Buckman MS, Sordella R, Karoly ED, Mohney R, Stiles BM, Elemento O, Altorki NK, and McGraw TE. Metabolic alterations in lung cancer-associated fibroblasts correlated with increased glycolytic metabolism of the tumor. Mol Cancer Res 11: 579-592, 2013
32. Chen J, Li Y, Yu TS, McKay RM, Burns DK, Kernie SG, and Parada LF. A restricted cell population propagates glioblastoma growth after chemotherapy. Nature 488: 522-526, 2012
33. Chen X, Qian Y, and Wu S. The Warburg effect: evolving interpretations of an established concept. Free Radic Biol Med 79: 253-263, 2015
34. Cheng SC, Quintin J, Cramer RA, Shepardson KM, Saeed S, Kumar V, Giamarellos-Bourboulis EJ, Martens JH, Rao NA, Aghajanirefah A, Manjeri GR, Li Y, Ifrim DC, Arts RJ, van der Veer BM, Deen PM, Logie C, O?Neill LA, Willems P, van de Veerdonk FL, van der Meer JW, Ng A, Joosten LA, Wijmenga C, Stunnenberg HG, Xavier RJ, and Netea MG. mTOR-and HIF-1alpha-mediated aerobic glycolysis as metabolic basis for trained immunity. Science 345: 1250684, 2014
35. Choudhary C, Kumar C, Gnad F, Nielsen ML, Rehman M, Walther TC, Olsen JV, and Mann M. Lysine acetylation targets protein complexes and co-regulates major cellular functions. Science 325: 834-840, 2009
36. Costa A, Scholer-Dahirel A, and Mechta-Grigoriou F. The role of reactive oxygen species and metabolism on cancer cells and their microenvironment. Semin Cancer Biol 25: 23-32, 2014
37. Csibi A, Lee G, Yoon SO, Tong H, Ilter D, Elia I, Fendt SM, Roberts TM, and Blenis J. The mTORC1/S6K1 pathway regulates glutamine metabolism through the eIF4B-dependent control of c-Myc translation. Curr Biol 24: 2274-2280, 2014
38. Currie E, Schulze A, Zechner R, Walther TC, and Farese RV, Jr. Cellular fatty acid metabolism and cancer. Cell Metab 18: 153-161, 2013
39. Dang L, White DW, Gross S, Bennett BD, Bittinger MA, Driggers EM, Fantin VR, Jang HG, Jin S, Keenan MC, Marks KM, Prins RM, Ward PS, Yen KE, Liau LM, Rabinowitz JD, Cantley LC, Thompson CB, Vander Heiden MG, and Su SM. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 462: 739-744, 2009
40. DeBerardinis RJ and Cheng T. Q?s next: the diverse functions of glutamine in metabolism, cell biology and cancer. Oncogene 29: 313-324, 2010
41. DeBerardinis RJ, Lum JJ, Hatzivassiliou G, and Thompson CB. The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. Cell Metab 7: 11-20, 2008
42. Deblois G, St-Pierre J, and Giguere V. The PGC-1/ERR signaling axis in cancer. Oncogene 32: 3483-3490, 2013
43. Delgoffe GM, Pollizzi KN, Waickman AT, Heikamp E, Meyers DJ, HortonMR, Xiao B, Worley PF, and Powell JD. The kinase mTOR regulates the differentiation of helper T cells through the selective activation of signaling by mTORC1 and mTORC2. Nat Immunol 12: 295-303, 2011
44. DeNicola GM, Chen PH, Mullarky E, Sudderth JA, Hu Z, Wu D, Tang H, Xie Y, Asara JM, Huffman KE, Wistuba, II, Minna JD, DeBerardinis RJ, and Cantley LC. NRF2 regulates serine biosynthesis in non-small cell lung cancer. Nat Genet 47: 1475-1481, 2015
45. Dupuy F, Tabaries S, Andrzejewski S, Dong Z, Blagih J, Annis MG, Omeroglu A, Gao D, Leung S, Amir E, Clemons M, Aguilar-Mahecha A, Basik M, Vincent EE, St-Pierre J, Jones RG, and Siegel PM. PDK1-dependent metabolic reprogramming dictates metastatic potential in breast cancer. Cell Metab 22: 577-589, 2015
46. ErezN,TruittM,OlsonP, ArronST, andHanahanD. Cancerassociated fibroblasts are activated in incipient neoplasia to orchestrate tumor-promoting inflammation in anNF-kappaBdependent manner. Cancer Cell 17: 135-147, 2010
47. Evans MJ and Scarpulla RC. Interaction of nuclear factors with multiple sites in the somatic cytochrome c promoter. Characterization of upstream NRF-1, ATF, and intron Sp1 recognition sequences. J Biol Chem264: 14361-14368, 1989
48. Fantin VR, St-Pierre J, and Leder P. Attenuation of LDHA expression uncovers a link between glycolysis, mitochondrial physiology, and tumor maintenance. Cancer Cell 9: 425-434, 2006
49. Feig C, Jones JO, Kraman M, Wells RJ, Deonarine A, Chan DS, Connell CM, Roberts EW, Zhao Q, Caballero OL, Teichmann SA, Janowitz T, Jodrell DI, Tuveson DA, and Fearon DT. Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PDL1 immunotherapy in pancreatic cancer. Proc Natl Acad Sci U S A 110: 20212-20217, 2013
50. Feilchenfeldt J, Brundler MA, Soravia C, Totsch M, and Meier CA. Peroxisome proliferator-activated receptors (PPARs) and associated transcription factors in colon cancer: reduced expression of PPARgamma-coactivator 1 (PGC-1). Cancer Lett 203: 25-33, 2004
51. Feng W, Gentles A, Nair RV, Huang M, Lin Y, Lee CY, Cai S, Scheeren FA, Kuo AH, and Diehn M. Targeting unique metabolic properties of breast tumor initiating cells. Stem Cells 32: 1734-1745, 2014
52. Fiaschi T, Marini A, Giannoni E, Taddei ML, Gandellini P, De Donatis A, Lanciotti M, Serni S, Cirri P, and Chiarugi P. Reciprocal metabolic reprogramming through lactate shuttle coordinately influences tumor-stroma interplay. Cancer Res 72: 5130-5140, 2012
53. Finlay DK, Rosenzweig E, Sinclair LV, Feijoo-Carnero C, Hukelmann JL, Rolf J, Panteleyev AA, Okkenhaug K, and Cantrell DA. PDK1 regulation of mTOR and hypoxiainducible factor 1 integrate metabolism and migration of CD8+ T cells. J Exp Med 209: 2441-2453, 2012
54. Finn RS, Dering J, Conklin D, Kalous O, Cohen DJ, Desai AJ, Ginther C, Atefi M, Chen I, Fowst C, Los G, and Slamon DJ. PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro. Breast Cancer Res 11: R77, 2009
55. Fiori A, Perez-Martinez X, and Fox TD. Overexpression of the COX2 translational activator, Pet111p, prevents translation of COX1 mRNA and cytochrome c oxidase assembly in mitochondria of Saccharomyces cerevisiae. Mol Microbiol 56: 1689-1704, 2005
56. Frantz C, Stewart KM, and Weaver VM. The extracellular matrix at a glance. J Cell Sci 123: 4195-4200, 2010
57. Frauwirth KA, Riley JL, Harris MH, Parry RV, Rathmell JC, Plas DR, Elstrom RL, June CH, and Thompson CB. The CD28 signaling pathway regulates glucose metabolism. Immunity 16: 769-777, 2002
58. Frezza C and Gottlieb E. Mitochondria in cancer: not just innocent bystanders. Semin Cancer Biol 19: 4-11, 2009
59. Fujino T, Kondo J, Ishikawa M, Morikawa K, and Yamamoto TT. Acetyl-CoA synthetase 2, a mitochondrial matrix enzyme involved in the oxidation of acetate. J Biol Chem 276: 11420-11426, 2001
60. Galvan-Pena S and O?Neill LA. Metabolic reprograming in macrophage polarization. Front Immunol 5: 420, 2014
61. Gao P, Tchernyshyov I, Chang TC, Lee YS, Kita K, Ochi T, Zeller KI, De Marzo AM, Van Eyk JE, Mendell JT, and Dang CV. c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism. Nature 458: 762-765, 2009
62. Gasparre G, Porcelli AM, Lenaz G, and Romeo G. Relevance of mitochondrial genetics and metabolism in cancer development. Cold Spring Harbor Perspect Biol 5, 2013
63. Gatenby RA and Gillies RJ. Why do cancers have high aerobic glycolysis? Nat Rev Cancer 4: 891-899, 2004
64. Gentric G, Maillet V, Paradis V, Couton D, L?Hermitte A, Panasyuk G, Fromenty B, Celton-Morizur S, and Desdouets C. Oxidative stress promotes pathologic polyploidization in nonalcoholic fatty liver disease. J Clin Invest 125: 981-992, 2015
65. Gerald D, Berra E, Frapart YM, Chan DA, Giaccia AJ, Mansuy D, Pouyssegur J, Yaniv M, and Mechta-Grigoriou F. JunD reduces tumor angiogenesis by protecting cells from oxidative stress. Cell 118: 781-794, 2004
66. Giannoni E, Bianchini F, Calorini L, and Chiarugi P. Cancer associated fibroblasts exploit reactive oxygen species through a proinflammatory signature leading to epithelial mesenchymal transition and stemness. Antioxid Redox Signal 14: 2361-2371, 2011
67. Giannoni E, Taddei ML, Morandi A, Comito G, Calvani M, Bianchini F, Richichi B, Raugei G, Wong N, Tang D, and Chiarugi P. Targeting stromal-induced pyruvate kinase M2 nuclear translocation impairs oxphos and prostate cancer metastatic spread. Oncotarget 6: 24061-24074, 2015
68. Gleyzer N, Vercauteren K, and Scarpulla RC. Control of mitochondrial transcription specificity factors (TFB1M and TFB2M) by nuclear respiratory factors (NRF-1 and NRF-2) and PGC-1 family coactivators. Mol Cell Biol 25: 1354-1366, 2005
69. Goetz JG, Minguet S, Navarro-Lerida I, Lazcano JJ, Samaniego R, Calvo E, Tello M, Osteso-Ibanez T, Pellinen T, Echarri A, Cerezo A, Klein-Szanto AJ, Garcia R, Keely PJ, Sanchez-Mateos P, Cukierman E, and Del Pozo MA. Biomechanical remodeling of the microenvironment by stromal caveolin-1 favors tumor invasion and metastasis. Cell 146: 148-163, 2011
70. Gogvadze V, Orrenius S, and Zhivotovsky B. Mitochondria in cancer cells: what is so special about them? Trends Cell Biol 18: 165-173, 2008
71. Gordon S and Taylor PR. Monocyte and macrophage heterogeneity. Nat Rev Immunol 5: 953-964, 2005
72. Grohmann K, Amairic F, Crews S, and Attardi G. Failure to detect cap structures in mitochondrial DNA-coded poly(A)-containing RNA from HeLa cells. Nucleic Acids Res 5: 637-651, 1978
73. Gugneja S, Virbasius CM, and Scarpulla RC. Nuclear respiratory factors 1 and 2 utilize similar glutaminecontaining clusters of hydrophobic residues to activate transcription. Mol Cell Biol 16: 5708-5716, 1996
74. Guppy M, Leedman P, Zu X, and Russell V. Contribution by different fuels and metabolic pathways to the total ATP turnover of proliferating MCF-7 breast cancer cells. Biochem J 364: 309-315, 2002
75. Haigis MC and Sinclair DA. Mammalian sirtuins: biological insights and disease relevance. Ann Rev Pathol 5: 253-295, 2010
76. HallowsWC, Yu W, and Denu JM. Regulation of glycolytic enzyme phosphoglycerate mutase-1 by Sirt1 proteinmediated deacetylation. J Biol Chem 287: 3850-3858, 2012
77. Hanahan D and Weinberg RA. Hallmarks of cancer: the next generation. Cell 144: 646-674, 2011
78. Haq R, Yokoyama S, Hawryluk EB, Jonsson GB, Frederick DT, McHenry K, Porter D, Tran TN, Love KT, Langer R, Anderson DG, Garraway LA, Duncan LM, Morton DL, Hoon DS, Wargo JA, Song JS, and Fisher DE. BCL2A1 is a lineage-specific antiapoptotic melanoma oncogene that confers resistance to BRAF inhibition. Proc Natl Acad Sci USA 110: 4321-4326, 2013
79. Hard GC. Some biochemical aspects of the immune macrophage. Br J Exp Pathol 51: 97-105, 1970
80. Haxhinasto S, Mathis D, and Benoist C. The AKT-mTOR axis regulates de novo differentiation of CD4+Foxp3+ cells. J Exp Med 205: 565-574, 2008
81. He W, Newman JC, Wang MZ, Ho L, and Verdin E. Mitochondrial sirtuins: regulators of protein acylation and metabolism. Trends Endocrinol Metab 23: 467-476, 2012
82. Herrmann JM, Woellhaf MW, and Bonnefoy N. Control of protein synthesis in yeast mitochondria: the concept of translational activators. Biochim Biophys Acta 1833: 286-294, 2013
83. Ho PC, Bihuniak JD, Macintyre AN, Staron M, Liu X, Amezquita R, Tsui YC, Cui G, Micevic G, Perales JC, Kleinstein SH, Abel ED, Insogna KL, Feske S, Locasale JW, Bosenberg MW, Rathmell JC, and Kaech SM. Phosphoenolpyruvate is a metabolic checkpoint of antitumor T cell responses. Cell 162: 1217-1228, 2015
84. Horecker BL. The pentose phosphate pathway. J Biol Chem 277: 47965-47971, 2002
85. Horwich AL, Kalousek F, Mellman I, and Rosenberg LE. A leader peptide is sufficient to direct mitochondrial import of a chimeric protein. EMBO J 4: 1129-1135, 1985
86. Huang SC, Everts B, Ivanova Y, O?Sullivan D, Nascimento M, Smith AM, Beatty W, Love-Gregory L, Lam WY, O?Neill CM, Yan C, Du H, Abumrad NA, Urban JF, Jr., Artyomov MN, Pearce EL, and Pearce EJ. Cell-intrinsic lysosomal lipolysis is essential for alternative activation of macrophages. Nat Immunol 15: 846-855, 2014
87. Iborra FJ, Kimura H, and Cook PR. The functional organization of mitochondrial genomes in human cells. BMC Biol 2: 9, 2004
88. Ito K and Suda T. Metabolic requirements for the maintenance of self-renewing stem cells. Nat Rev Mol Cell Biol 15: 243-256, 2014
89. Jager S, Handschin C, St-Pierre J, and Spiegelman BM. AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1alpha. Proc Natl Acad Sci USA 104: 12017-12022, 2007
90. Janiszewska M, Suva ML, Riggi N, Houtkooper RH, Auwerx J, Clement-Schatlo V, Radovanovic I, Rheinbay E, Provero P, and Stamenkovic I. Imp2 controls oxidative phosphorylation and is crucial for preserving glioblastoma cancer stem cells. Genes Dev 26: 1926-1944, 2012
91. Jeninga EH, Schoonjans K, and Auwerx J. Reversible acetylation of PGC-1: connecting energy sensors and effectors to guarantee metabolic flexibility. Oncogene 29: 4617-4624, 2010
92. Jezierska-Drutel A, Rosenzweig SA, and Neumann CA. Role of oxidative stress and the microenvironment in breast cancer development and progression. Adv Cancer Res 119: 107-125, 2013
93. Jha AK, Huang SC, Sergushichev A, Lampropoulou V, Ivanova Y, Loginicheva E, Chmielewski K, Stewart KM, Ashall J, Everts B, Pearce EJ, Driggers EM, and Artyomov MN. Network integration of parallel metabolic and transcriptional data reveals metabolic modules that regulate macrophage polarization. Immunity 42: 419-430, 2015
94. Jones RG and Thompson CB. Revving the engine: signal transduction fuels T cell activation. Immunity 27: 173-178, 2007
95. Jose C, Bellance N, and Rossignol R. Choosing between glycolysis and oxidative phosphorylation: a tumor?s dilemma? Biochim Biophys Acta 1807: 552-561, 2011
96. Joyce JA and Fearon DT. T cell exclusion, immune privilege, and the tumor microenvironment. Science 348: 74-80, 2015
97. Kalhan SC and Hanson RW. Resurgence of serine: an often neglected but indispensable amino Acid. J Biol Chem 287: 19786-19791, 2012
98. Kaminski MM, Sauer SW, Kaminski M, Opp S, Ruppert T, Grigaravicius P, Grudnik P, Grone HJ, Krammer PH, and Gulow K. T cell activation is driven by an ADPdependent glucokinase linking enhanced glycolysis with mitochondrial reactive oxygen species generation. Cell Rep 2: 1300-1315, 2012
99. Kaminski MM, Sauer SW, Klemke CD, Suss D, Okun JG, Krammer PH, and Gulow K. Mitochondrial reactive oxygen species control T cell activation by regulating IL-2 and IL-4 expression: mechanism of ciprofloxacin-mediated immunosuppression. J Immunol 184: 4827-4841, 2010
100. Karagiannis GS, Poutahidis T, Erdman SE, Kirsch R, Riddell RH, and Diamandis EP. Cancer-associated fibroblasts drive the progression of metastasis through both paracrine and mechanical pressure on cancer tissue. Mol Cancer Res 10: 1403-1418, 2012
101. Kelly B and O?Neill LA. Metabolic reprogramming in macrophages and dendritic cells in innate immunity. Cell Res 25: 771-784, 2015
102. Kelly DP and Scarpulla RC. Transcriptional regulatory circuits controlling mitochondrial biogenesis and function. Genes Dev 18: 357-368, 2004
103. Kim JW, Tchernyshyov I, Semenza GL, and Dang CV. HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab 3: 177-185, 2006
104. King MP and Attardi G. Human cells lacking mtDNA: repopulation with exogenous mitochondria by complementation. Science 246: 500-503, 1989
105. Klysz D, Tai X, Robert PA, Craveiro M, Cretenet G, Oburoglu L, Mongellaz C, Floess S, Fritz V, Matias MI, Yong C, Surh N, Marie JC, Huehn J, Zimmermann V, Kinet S, Dardalhon V, and Taylor N. Glutaminedependent alpha-ketoglutarate production regulates the balance between T helper 1 cell and regulatory T cell generation. Sci Signal 8: ra97, 2015
106. Krebs HA, Ruffo A, JohnsonM, Eggleston LV, and Hems R. Oxidative phosphorylation. Biochem J 54: 107-116, 1953
107. Kung HN, Marks JR, and Chi JT. Glutamine synthetase is a genetic determinant of cell type-specific glutamine independence in breast epithelia. PLoS Genet 7: e1002229, 2011
108. Lagadinou ED, Sach A, Callahan K, Rossi RM, Neering SJ, Minhajuddin M, Ashton JM, Pei S, Grose V, O?Dwyer KM, Liesveld JL, Brookes PS, Becker MW, and Jordan CT. BCL-2 inhibition targets oxidative phosphorylation and selectively eradicates quiescent human leukemia stem cells. Cell Stem Cell 12: 329-341, 2013
109. Lapeire L, Hendrix A, Lambein K, Van Bockstal M, Braems G, Van Den Broecke R, Limame R, Mestdagh P, Vandesompele J, Vanhove C, Maynard D, Lehuede C, Muller C, Valet P, Gespach CP, Bracke M, Cocquyt V, Denys H, and De Wever O. Cancer-associated adipose tissue promotes breast cancer progression by paracrine oncostatin M and Jak/STAT3 signaling. Cancer Res 74: 6806-6819, 2014
110. Laplante M and Sabatini DM. mTOR signaling in growth control and disease. Cell 149: 274-293, 2012
111. Laurent G, Solari F, Mateescu B, Karaca M, Castel J, Bourachot B, Magnan C, Billaud M, and Mechta-Grigoriou F. Oxidative stress contributes to aging by enhancing pancreatic angiogenesis and insulin signaling. Cell Metab 7: 113-124, 2008
112. LeBleu VS, O?Connell JT, Gonzalez Herrera KN, Wikman H, Pantel K, Haigis MC, de Carvalho FM, Damascena A, Domingos Chinen LT, Rocha RM, Asara JM, and Kalluri R. PGC-1alpha mediates mitochondrial biogenesis and oxidative phosphorylation in cancer cells to promote metastasis. Nat Cell Biol 16: 992-1003, 1001-1015, 2014
113. Lefort S, Joffre C, Kieffer Y, Givel AM, Bourachot B, Zago G, Bieche I, Dubois T, Meseure D, Vincent-Salomon A, Camonis J, and Mechta-Grigoriou F. Inhibition of autophagy as a new means of improving chemotherapy efficiency in high-LC3B triple-negative breast cancers. Autophagy 10: 2122-2142, 2014
114. Lemons JM, Feng XJ, Bennett BD, Legesse-Miller A, Johnson EL, Raitman I, Pollina EA, Rabitz HA, Rabinowitz JD, and Coller HA. Quiescent fibroblasts exhibit high metabolic activity. PLoS Biol 8: e1000514, 2010
115. Levine AJ and Puzio-Kuter AM. The control of the metabolic switch in cancers by oncogenes and tumor suppressor genes. Science 330: 1340-1344, 2010
116. Li F, Wang Y, Zeller KI, Potter JJ, Wonsey DR, O?Donnell KA, Kim JW, Yustein JT, Lee LA, and Dang CV. Myc stimulates nuclearly encoded mitochondrial genes and mitochondrial biogenesis. Mol Cell Biol 25: 6225-6234, 2005
117. Liao HX and Spremulli LL. Interaction of bovine mitochondrial ribosomes with messenger RNA. J Biol Chem 264: 7518-7522, 1989
118. Lim JH, Luo C, Vazquez F, and Puigserver P. Targeting mitochondrial oxidative metabolism in melanoma causes metabolic compensation through glucose and glutamine utilization. Cancer Res 74: 3535-3545, 2014
119. Lin J, Puigserver P, Donovan J, Tarr P, and Spiegelman BM. Peroxisome proliferator-activated receptor gamma coactivator 1beta (PGC-1beta), a novel PGC-1-related transcription coactivator associated with host cell factor. J Biol Chem 277: 1645-1648, 2002
120. Lin X, Zheng W, Liu J, Zhang Y, Qin H, Wu H, Xue B, Lu Y, and Shen P. Oxidative stress in malignant melanoma enhances tumor necrosis factor-alpha secretion of tumor-associated macrophages that promote cancer cell invasion. Antioxid Redox Signal 19: 1337-1355, 2013
121. Liu W, Le A, Hancock C, Lane AN, Dang CV, Fan TW, and Phang JM. Reprogramming of proline and glutamine metabolism contributes to the proliferative and metabolic responses regulated by oncogenic transcription factor c-MYC. Proc Natl Acad Sci USA 109: 8983-8988, 2012
122. Locasale JW. Serine, glycine and one-carbon units: cancer metabolismin full circle. NatRev Cancer 13: 572-583, 2013
123. Locasale JW, Grassian AR, Melman T, Lyssiotis CA, Mattaini KR, Bass AJ, Heffron G, Metallo CM, Muranen T, Sharfi H, Sasaki AT, Anastasiou D, Mullarky E, Vokes NI, Sasaki M, Beroukhim R, Stephanopoulos G, Ligon AH, Meyerson M, Richardson AL, Chin L, Wagner G, Asara JM, Brugge JS, Cantley LC, and Vander Heiden MG. Phosphoglycerate dehydrogenase diverts glycolytic flux and contributes to oncogenesis. Nat Genet 43: 869-874, 2011
124. Lopez-Mejia IC and Fajas L. Cell cycle regulation of mitochondrial function. Curr Opin Cell Biol 33: 19-25, 2015
125. Maddocks OD, Berkers CR, Mason SM, Zheng L, Blyth K, Gottlieb E, and Vousden KH. Serine starvation induces stress and p53-dependent metabolic remodelling in cancer cells. Nature 493: 542-546, 2013
126. Mantovani A, Sozzani S, Locati M, Allavena P, and Sica A. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol 23: 549-555, 2002
127. Marin-Valencia I, Yang C, Mashimo T, Cho S, Baek H, Yang XL, Rajagopalan KN, Maddie M, Vemireddy V, Zhao Z, Cai L, Good L, Tu BP, Hatanpaa KJ, Mickey BE, Mates JM, Pascual JM, Maher EA, Malloy CR, Deberardinis RJ, and Bachoo RM. Analysis of tumor metabolism reveals mitochondrial glucose oxidation in genetically diverse human glioblastomas in the mouse brain in vivo. Cell Metab 15: 827-837, 2012
128. Martinez-Outschoorn UE, Sotgia F, and Lisanti MP. Caveolae and signalling in cancer. Nat Rev Cancer 15: 225-237, 2015
129. McCulloch V, Seidel-Rogol BL, and Shadel GS. A human mitochondrial transcription factor is related to RNA adenine methyltransferases and binds S-adenosylmethionine. Mol Cell Biol 22: 1116-1125, 2002
130. McInerney EM, Rose DW, Flynn SE, Westin S, Mullen TM, Krones A, Inostroza J, Torchia J, Nolte RT, Assa-Munt N, Milburn MV, Glass CK, and Rosenfeld MG. Determinants of coactivator LXXLL motif specificity in nuclear receptor transcriptional activation. Genes Dev 12: 3357-3368, 1998
131. Medici D and Kalluri R. Endothelial-mesenchymal transition and its contribution to the emergence of stem cell phenotype. Semin Cancer Biol 22: 379-384, 2012
132. Mercier I, Camacho J, Titchen K, Gonzales DM, Quann K, Bryant KG, Molchansky A, Milliman JN, Whitaker-Menezes D, Sotgia F, Jasmin JF, Schwarting R, Pestell RG, Blagosklonny MV, and Lisanti MP. Caveolin-1 and accelerated host aging in the breast tumor microenvironment: chemoprevention with rapamycin, an mTOR inhibitor and anti-aging drug. Am J Pathol 181: 278-293, 2012
133. Michalek RD, Gerriets VA, Jacobs SR, Macintyre AN, MacIver NJ, Mason EF, Sullivan SA, Nichols AG, and Rathmell JC. Cutting edge: distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4+ T cell subsets. J Immunol 186: 3299-3303, 2011
134. Michaud M, Martins I, Sukkurwala AQ, Adjemian S, Ma Y, Pellegatti P, Shen S, Kepp O, Scoazec M, Mignot G, Rello-Varona S, Tailler M, Menger L, Vacchelli E, Galluzzi L, Ghiringhelli F, di Virgilio F, Zitvogel L, and Kroemer G. Autophagy-dependent anticancer immune responses induced by chemotherapeutic agents in mice. Science 334: 1573-1577, 2011
135. Michelakis ED, Sutendra G, Dromparis P, Webster L, Haromy A, Niven E, Maguire C, Gammer TL, Mackey JR, Fulton D, Abdulkarim B, McMurtry MS, and Petruk KC. Metabolic modulation of glioblastoma with dichloroacetate. Sci Transl Med 2: 31ra34, 2010
136. Mitra K, Wunder C, Roysam B, Lin G, and Lippincott-Schwartz J. A hyperfused mitochondrial state achieved at G1-S regulates cyclin E buildup and entry into S phase. Proc Natl Acad Sci USA 106: 11960-11965, 2009
137. Monti S, Savage KJ, Kutok JL, Feuerhake F, Kurtin P, Mihm M, Wu B, Pasqualucci L, Neuberg D, Aguiar RC, Dal Cin P, Ladd C, Pinkus GS, Salles G, Harris NL, Dalla-Favera R, Habermann TM, Aster JC, Golub TR, and Shipp MA. Molecular profiling of diffuse large B-cell lymphoma identifies robust subtypes including one characterized by host inflammatory response. Blood 105: 1851-1861, 2005
138. Moreno-Sanchez R, Rodriguez-Enriquez S, Marin-Hernandez A, and Saavedra E. Energy metabolism in tumor cells. FEBS J 274: 1393-1418, 2007
139. Moreno-Sanchez R, Rodriguez-Enriquez S, Saavedra E, Marin-Hernandez A, and Gallardo-Perez JC. The bioenergetics of cancer: is glycolysis the main ATP supplier in all tumor cells? Biofactors 35: 209-225, 2009
140. Morita M, Gravel SP, Chenard V, Sikstrom K, Zheng L, Alain T, Gandin V, Avizonis D, Arguello M, Zakaria C, McLaughlan S, Nouet Y, Pause A, Pollak M, Gottlieb E, Larsson O, St-Pierre J, Topisirovic I, and Sonenberg N. mTORC1 controls mitochondrial activity and biogenesis through 4E-BP-dependent translational regulation. Cell Metab 18: 698-711, 2013
141. Murphy MP, Holmgren A, Larsson NG, Halliwell B, Chang CJ, Kalyanaraman B, Rhee SG, Thornalley PJ, Partridge L, Gems D, Nystrom T, Belousov V, Schumacker PT, and Winterbourn CC. Unraveling the biological roles of reactive oxygen species. Cell Metab 13: 361-366, 2011
142. Nagley P. Coordination of gene expression in the formation of mammalian mitochondria. Trends Genet 7: 1-4, 1991
143. Nahon P, Sutton A, Pessayre D, Rufat P, Degoul F, Ganne-Carrie N, Ziol M, Charnaux N, N?Kontchou G, Trinchet JC, Gattegno L, and Beaugrand M. Genetic dimorphism in superoxide dismutase and susceptibility to alcoholic cirrhosis, hepatocellular carcinoma, and death. Clin Gastroenterol Hepatol 3: 292-298, 2005
144. Nelson DL and Cox MM. Lehninger, Principles of Biochemistry. 6th edition.NewYork,NY: W.H. Freeman, 2013
145. Newsholme P, Procopio J, Lima MM, Pithon-Curi TC, and Curi R. Glutamine and glutamate-their central role in cell metabolism and function. Cell Biochem Funct 21: 1-9, 2003
146. Noy R and Pollard JW. Tumor-associated macrophages: from mechanisms to therapy. Immunity 41: 49-61, 2014
147. Obre E and Rossignol R. Emerging concepts in bioenergetics and cancer research: metabolic flexibility, coupling, symbiosis, switch, oxidative tumors, metabolic remodeling, signaling and bioenergetic therapy. Int J Biochem Cell Biol 59: 167-181, 2015
148. Odegaard JI and Chawla A. Alternative macrophage activation and metabolism. Ann Rev Pathol 6: 275-297, 2011
149. Ohlund D, Elyada E, and Tuveson D. Fibroblast heterogeneity in the cancer wound. J ExpMed 211: 1503-1523, 2014
150. Ojala D, Montoya J, and Attardi G. tRNA punctuation model of RNA processing in human mitochondria. Nature 290: 470-474, 1981
151. Okoye I, Wang L, Pallmer K, Richter K, Ichimura T, Haas R, Crouse J, Choi O, Heathcote D, Lovo E, Mauro C, Abdi R, Oxenius A, Rutschmann S, and Ashton-Rickardt PG. T cell metabolism. The protein LEM promotes CD8(+) T cell immunity through effects on mitochondrial respiration. Science 348: 995-1001, 2015
152. Ozaki A, Tanimoto T, and Saji S. Palbociclib in Hormone-Receptor-Positive Advanced Breast Cancer. N Engl J Med 373: 1672-1673, 2015
153. Paget S. The distribution of secondary growths in cancer of the breast. Lancet 133: 571-573, 1889
154. Panopoulos AD, Yanes O, Ruiz S, Kida YS, Diep D, Tautenhahn R, Herrerias A, Batchelder EM, Plongthongkum N, Lutz M, Berggren WT, Zhang K, Evans RM, Siuzdak G, and Izpisua Belmonte JC. The metabolome of induced pluripotent stem cells reveals metabolic changes occurring in somatic cell reprogramming. Cell Res 22: 168-177, 2012
155. Papandreou I, Cairns RA, Fontana L, Lim AL, and Denko NC. HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption. Cell Metab 3: 187-197, 2006
156. Parker GC, Acsadi G, and Brenner CA. Mitochondria: determinants of stem cell fate? Stem Cells Dev 18: 803-806, 2009
157. Parri M and Chiarugi P. Redox molecular machines involved in tumor progression. Antioxid Redox Signal 19: 1828-1845, 2013
158. Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Siu IM, Gallia GL, Olivi A, McLendon R, Rasheed BA, Keir S, Nikolskaya T, Nikolsky Y, Busam DA, Tekleab H, Diaz LA, Jr., Hartigan J, Smith DR, Strausberg RL, Marie SK, Shinjo SM, Yan H, Riggins GJ, Bigner DD, Karchin R, Papadopoulos N, Parmigiani G, Vogelstein B, Velculescu VE, and Kinzler KW. An integrated genomic analysis of human glioblastoma multiforme. Science 321: 1807-1812, 2008
159. Pasto A, Bellio C, Pilotto G, Ciminale V, Silic-Benussi M, Guzzo G, Rasola A, Frasson C, Nardo G, Zulato E, Nicoletto MO, Manicone M, Indraccolo S, and Amadori A. Cancer stem cells from epithelial ovarian cancer patients privilege oxidative phosphorylation, and resist glucose deprivation. Oncotarget 5: 4305-4319, 2014
160. Pavlides S, Whitaker-Menezes D, Castello-Cros R, Flomenberg N,Witkiewicz AK, Frank PG, Casimiro MC,Wang C, Fortina P, Addya S, Pestell RG, Martinez-Outschoorn UE, Sotgia F, and Lisanti MP. The reverse Warburg effect: aerobic glycolysis in cancer associated fibroblasts and the tumor stroma. Cell Cycle 8: 3984-4001, 2009
161. Pike LS, Smift AL, Croteau NJ, Ferrick DA, and Wu M. Inhibition of fatty acid oxidation by etomoxir impairs NADPH production and increases reactive oxygen species resulting in ATP depletion and cell death in human glioblastoma cells. Biochim Biophys Acta 1807: 726-734, 2011
162. Possemato R, Marks KM, Shaul YD, Pacold ME, Kim D, Birsoy K, Sethumadhavan S, Woo HK, Jang HG, Jha AK, Chen WW, Barrett FG, Stransky N, Tsun ZY, Cowley GS, Barretina J, Kalaany NY, Hsu PP, Ottina K, Chan AM, Yuan B, Garraway LA, Root DE, Mino-Kenudson M, Brachtel EF, Driggers EM, and Sabatini DM. Functional genomics reveal that the serine synthesis pathway is essential in breast cancer. Nature 476: 346-350, 2011
163. Pouyssegur J and Mechta-Grigoriou F. Redox regulation of the hypoxia-inducible factor. Biol Chem 387: 1337-1346, 2006
164. Puigserver P, Wu Z, Park CW, Graves R, Wright M, and Spiegelman BM. A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell 92: 829-839, 1998
165. Quail DF and Joyce JA. Microenvironmental regulation of tumor progression and metastasis. Nat Med 19: 1423-1437, 2013
166. Radisky DC, Levy DD, Littlepage LE, Liu H, Nelson CM, Fata JE, Leake D, Godden EL, Albertson DG, Nieto MA, Werb Z, and Bissell MJ. Rac1b and reactive oxygen species mediate MMP-3-induced EMT and genomic instability. Nature 436: 123-127, 2005
167. Rao RR, Li Q, Odunsi K, and Shrikant PA. The mTOR kinase determines effector versus memory CD8+ T cell fate by regulating the expression of transcription factors T-bet and Eomesodermin. Immunity 32: 67-78, 2010
168. Rapaport D. Finding the right organelle. Targeting signals in mitochondrial outer-membrane proteins. EMBO Rep 4: 948-952, 2003
169. Rattigan YI, Patel BB, Ackerstaff E, Sukenick G, Koutcher JA, Glod JW, and Banerjee D. Lactate is a mediator of metabolic cooperation between stromal carcinoma associated fibroblasts and glycolytic tumor cells in the tumor microenvironment. Exp Cell Res 318: 326-335, 2012
170. Reitzer LJ, Wice BM, and Kennell D. Evidence that glutamine, not sugar, is the major energy source for cultured HeLa cells. J Biol Chem 254: 2669-2676, 1979
171. Rodgers JT, Lerin C, Haas W, Gygi SP, Spiegelman BM, and Puigserver P. Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1. Nature 434: 113-118, 2005
172. Rodriguez-Prados JC, Traves PG, Cuenca J, Rico D, Aragones J, Martin-Sanz P, Cascante M, and Bosca L. Substrate fate in activated macrophages: a comparison between innate, classic, and alternative activation. J Immunol 185: 605-614, 2010
173. Roesch A, Vultur A, Bogeski I,Wang H, Zimmermann KM, Speicher D, Korbel C, Laschke MW, Gimotty PA, Philipp SE, Krause E, Patzold S, Villanueva J,Krepler C, Fukunaga-Kalabis M, Hoth M, Bastian BC, Vogt T, and Herlyn M. Overcoming intrinsic multidrug resistance in melanoma by blocking themitochondrial respiratory chain of slow-cycling JARID1B(high) cells. Cancer Cell 23: 811-825, 2013
174. Rorbach J, Richter R, Wessels HJ, Wydro M, Pekalski M, Farhoud M, Kuhl I, Gaisne M, Bonnefoy N, Smeitink JA, Lightowlers RN, and Chrzanowska-Lightowlers ZM. The human mitochondrial ribosome recycling factor is essential for cell viability. Nucleic Acids Res 36: 5787-5799, 2008
175. Rossi DJ, Jamieson CH, and Weissman IL. Stems cells and the pathways to aging and cancer. Cell 132: 681-696, 2008
176. Rossignol R, Gilkerson R, Aggeler R, Yamagata K, Remington SJ, and Capaldi RA. Energy substrate modulates mitochondrial structure and oxidative capacity in cancer cells. Cancer Res 64: 985-993, 2004
177. Rynne-Vidal A, Jimenez-Heffernan JA, Fernandez-Chacon C, Lopez-Cabrera M, and Sandoval P. The mesothelial origin of carcinoma associated-fibroblasts in peritoneal metastasis. Cancers 7: 1994-2011, 2015
178. Sakamaki T, Casimiro MC, Ju X, Quong AA, Katiyar S, Liu M, Jiao X, Li A, Zhang X, Lu Y, Wang C, Byers S, Nicholson R, Link T, Shemluck M, Yang J, Fricke ST, Novikoff PM, Papanikolaou A, Arnold A, Albanese C, and Pestell R. Cyclin D1 determines mitochondrial function in vivo. Mol Cell Biol 26: 5449-5469, 2006
179. Sancho P, Burgos-Ramos E, Tavera A, Bou Kheir T, Jagust P, Schoenhals M, Barneda D, Sellers K, Campos-Olivas R, Grana O, Viera CR, Yuneva M, Sainz B, Jr., and Heeschen C. MYC/PGC-1alpha Balance Determines the Metabolic Phenotype and Plasticity of Pancreatic Cancer Stem Cells. Cell Metab 22: 590-605, 2015
180. Sankaran VG, Orkin SH, and Walkley CR. Rb intrinsically promotes erythropoiesis by coupling cell cycle exit with mitochondrial biogenesis. Genes Dev 22: 463-475, 2008
181. Sauer LA, Stayman JW, 3rd, and Dauchy RT. Amino acid, glucose, and lactic acid utilization in vivo by rat tumors. Cancer Res 42: 4090-4097, 1982
182. Scarpulla RC. Metabolic control of mitochondrial biogenesis through the PGC-1 family regulatory network. Biochim Biophys Acta 1813: 1269-1278, 2011
183. Scarpulla RC. Nuclear control of respiratory chain expression by nuclear respiratory factors and PGC-1-related coactivator. Ann N Y Acad Sci 1147: 321-334, 2008
184. Schatz G. Mitochondria: beyond oxidative phosphorylation. Biochim Biophys Acta 1271: 123-126, 1995
185. Schoors S, Bruning U, Missiaen R, Queiroz KC, Borgers G, Elia I, Zecchin A, Cantelmo AR, Christen S, Goveia J, Heggermont W, Godde L, Vinckier S, Van Veldhoven PP, Eelen G, Schoonjans L, Gerhardt H, Dewerchin M, Baes M, De Bock K, Ghesquiere B, Lunt SY, Fendt SM, and Carmeliet P. Fatty acid carbon is essential for dNTP synthesis in endothelial cells. Nature 520: 192-197, 2015
186. Schreiber SN, Emter R, Hock MB, Knutti D, Cardenas J, Podvinec M, Oakeley EJ, and Kralli A. The estrogen-related receptor alpha (ERRalpha) functions in PPARgamma coactivator 1alpha (PGC-1alpha)-induced mitochondrial biogenesis. Proc Natl Acad Sci USA 101: 6472-6477, 2004
187. Schug ZT, Peck B, Jones DT, Zhang Q, Grosskurth S, Alam IS, Goodwin LM, Smethurst E, Mason S, Blyth K, McGarry L, James D, Shanks E, Kalna G, Saunders RE, JiangM, HowellM, Lassailly F, ThinMZ, Spencer-DeneB, Stamp G, van denBroekNJ,Mackay G,BulusuV, Kamphorst JJ, Tardito S, Strachan D, Harris AL, Aboagye EO, Critchlow SE, WakelamMJ, Schulze A, and Gottlieb E. Acetyl-CoA synthetase 2 promotes acetate utilization and maintains cancer cell growth under metabolic stress. Cancer Cell 27: 57-71, 2015
188. Sena LA, Li S, Jairaman A, Prakriya M, Ezponda T, Hildeman DA, Wang CR, Schumacker PT, Licht JD, Perlman H, Bryce PJ, and Chandel NS. Mitochondria are required for antigen-specific T cell activation through reactive oxygen species signaling. Immunity 38: 225-236, 2013
189. Shalapour S and Karin M. Immunity, inflammation, and cancer: an eternal fight between good and evil. J Clin Invest 125: 3347-3355, 2015
190. Shen XJ, Zhang H, Tang GS, Wang XD, Zheng R, Wang Y, Zhu Y, Xue XC, and Bi JW. Caveolin-1 is a modulator of fibroblast activation and a potential biomarker for gastric cancer. Int J Biol Sci 11: 370-379, 2015
191. Smeitink JA, Loeffen JL, Triepels RH, Smeets RJ, Trijbels JM, and van den Heuvel LP. Nuclear genes of human complex I of the mitochondrial electron transport chain: state of the art. Hum Mol Genet 7: 1573-1579, 1998
192. Smith-Garvin JE, Koretzky GA, and Jordan MS. T cell activation. Ann Rev Immunol 27: 591-619, 2009
193. Smits P, Smeitink J, and van den Heuvel L. Mitochondrial translation and beyond: processes implicated in combined oxidative phosphorylation deficiencies. J Biomed Biotechnol 2010: 737385, 2010
194. Smits P, Smeitink JA, van den Heuvel LP, Huynen MA, and Ettema TJ. Reconstructing the evolution of the mitochondrial ribosomal proteome. Nucleic Acids Res 35: 4686-4703, 2007
195. Soh H, Wasa M, and Fukuzawa M. Hypoxia upregulates amino acid transport in a human neuroblastoma cell line. J Pediatr Surg 42: 608-612, 2007
196. Sollner T, Rassow J, Wiedmann M, Schlossmann J, Keil P, Neupert W, and Pfanner N. Mapping of the protein import machinery in the mitochondrial outer membrane by crosslinking of translocation intermediates. Nature 355: 84-87, 1992
197. Son J, Lyssiotis CA, Ying H, Wang X, Hua S, Ligorio M, Perera RM, Ferrone CR, Mullarky E, Shyh-Chang N, Kang Y, Fleming JB, Bardeesy N, Asara JM, Haigis MC, DePinho RA, Cantley LC, and Kimmelman AC. Glutamine supports pancreatic cancer growth through a KRASregulated metabolic pathway. Nature 496: 101-105, 2013
198. Sosa V, Moline T, Somoza R, Paciucci R, Kondoh H, and ME LL. Oxidative stress and cancer: an overview. Ageing Res Rev 12: 376-390, 2013
199. St-Pierre J, Lin J, Krauss S, Tarr PT, Yang R, Newgard CB, and Spiegelman BM. Bioenergetic analysis of peroxisome proliferator-activated receptor gamma coactivators 1alpha and 1beta (PGC-1alpha and PGC-1beta) in muscle cells. J Biol Chem 278: 26597-26603, 2003
200. Suda T, Takubo K, and Semenza GL. Metabolic regulation of hematopoietic stem cells in the hypoxic niche. Cell Stem Cell 9: 298-310, 2011
201. Sullivan LB, Gui DY, Hosios AM, Bush LN, Freinkman E, and Vander Heiden MG. Supporting aspartate biosynthesis is an essential function of respiration in proliferating cells. Cell 162: 552-563, 2015
202. Sun RC and Denko NC. Hypoxic regulation of glutamine metabolism through HIF1 and SIAH2 supports lipid synthesis that is necessary for tumor growth. Cell Metab 19: 285-292, 2014
203. Sutton A, Imbert A, Igoudjil A, Descatoire V, Cazanave S, Pessayre D, and Degoul F. The manganese superoxide dismutase Ala16Val dimorphism modulates both mitochondrial import and mRNA stability. Pharmacogenetics Genomics 15: 311-319, 2005
204. Swietach P, Vaughan-Jones RD, and Harris AL. Regulation of tumor pH and the role of carbonic anhydrase 9. Cancer Metastasis Rev 26: 299-310, 2007
205. Taguchi N, Ishihara N, Jofuku A, Oka T, and Mihara K. Mitotic phosphorylation of dynamin-related GTPase Drp1 participates in mitochondrial fission. J Biol Chem 282: 11521-11529, 2007
206. Takakubo F, Cartwright P, Hoogenraad N, Thorburn DR, Collins F, Lithgow T, and Dahl HH. An amino acid substitution in the pyruvate dehydrogenase E1 alpha gene, affecting mitochondrial import of the precursor protein. Am J Hum Genet 57: 772-780, 1995
207. Tan Z, Xie N, Cui H, Moellering DR, Abraham E, Thannickal VJ, and Liu G. Pyruvate dehydrogenase kinase 1 participates in macrophage polarization via regulating glucose metabolism. J Immunol 194: 6082-6089, 2015
208. Tannahill GM, Curtis AM, Adamik J, Palsson-McDermott EM, McGettrick AF, Goel G, Frezza C, Bernard NJ, Kelly B, Foley NH, Zheng L, Gardet A, Tong Z, Jany SS, Corr SC, Haneklaus M, Caffrey BE, Pierce K, Walmsley S, Beasley FC, Cummins E, Nizet V, Whyte M, Taylor CT, Lin H, Masters SL, Gottlieb E, Kelly VP, Clish C, Auron PE, Xavier RJ, and O?Neill LA. Succinate is an inflammatory signal that induces IL-1beta through HIF-1alpha. Nature 496: 238-242, 2013
209. Terunuma A, Putluri N, Mishra P, Mathe EA, Dorsey TH, Yi M, Wallace TA, Issaq HJ, Zhou M, Killian JK, Stevenson HS, Karoly ED, Chan K, Samanta S, Prieto D, Hsu TY, Kurley SJ, Putluri V, Sonavane R, Edelman DC, Wulff J, Starks AM, Yang Y, Kittles RA, Yfantis HG, Lee DH, Ioffe OB, Schiff R, Stephens RM, Meltzer PS, Veenstra TD, Westbrook TF, Sreekumar A, and Ambs S. MYC-driven accumulation of 2-hydroxyglutarate is associated with breast cancer prognosis. J Clin Invest 124: 398-412, 2014
210. Timmerman LA, Holton T, Yuneva M, Louie RJ, Padro M, Daemen A, Hu M, Chan DA, Ethier SP, van ?t Veer LJ, Polyak K, McCormick F, and Gray JW. Glutamine sensitivity analysis identifies the xCT antiporter as a common triple-negative breast tumor therapeutic target. Cancer Cell 24: 450-465, 2013
211. Toullec A, Gerald D, Despouy G, Bourachot B, Cardon M, Lefort S, Richardson M, Rigaill G, Parrini MC, Lucchesi C, Bellanger D, Stern MH, Dubois T, Sastre-Garau X, Delattre O, Vincent-Salomon A, and Mechta-Grigoriou F. Oxidative stress promotes myofibroblast differentiation and tumour spreading. EMBO Mol Med 2: 211-230, 2010
212. Vander Heiden MG, Cantley LC, and Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324: 1029-1033, 2009
213. Vats D, Mukundan L, Odegaard JI, Zhang L, Smith KL, Morel CR, Wagner RA, Greaves DR, Murray PJ, and Chawla A. Oxidative metabolism and PGC-1beta attenuate macrophage-mediated inflammation. Cell Metab 4: 13-24, 2006
214. Vaupel P, Kallinowski F, and Okunieff P. Blood flow, oxygen and nutrient supply, and metabolic microenvironment of human tumors: a review. Cancer Res 49: 6449-6465, 1989
215. Vazquez F, Lim JH, Chim H, Bhalla K, Girnun G, Pierce K, Clish CB, Granter SR, Widlund HR, Spiegelman BM, and Puigserver P. PGC1alpha expression defines a subset of human melanoma tumors with increased mitochondrial capacity and resistance to oxidative stress. Cancer Cell 23: 287-301, 2013
216. Vercauteren K, Gleyzer N, and Scarpulla RC. Short hairpin RNA-mediated silencing of PRC (PGC-1-related coactivator) results in a severe respiratory chain deficiency associated with the proliferation of aberrant mitochondria. J Biol Chem 284: 2307-2319, 2009
217. Viale A, Pettazzoni P, Lyssiotis CA, Ying H, Sanchez N, Marchesini M, Carugo A, Green T, Seth S, Giuliani V, Kost-Alimova M, Muller F, Colla S, Nezi L, Genovese G, Deem AK, Kapoor A, Yao W, Brunetto E, Kang Y, Yuan M, Asara JM, Wang YA, Heffernan TP, Kimmelman AC, Wang H, Fleming JB, Cantley LC, DePinho RA, and Draetta GF. Oncogene ablation-resistant pancreatic cancer cells depend on mitochondrial function. Nature 514: 628-632, 2014
218. Villena JA and Kralli A. ERRalpha: a metabolic function for the oldest orphan. Trends Endocrinol Metab 19: 269-276, 2008
219. Virbasius JV and Scarpulla RC. Activation of the human mitochondrial transcription factor A gene by nuclear respiratory factors: a potential regulatory link between nuclear and mitochondrial gene expression in organelle biogenesis. Proc Natl Acad Sci USA 91: 1309-1313, 1994
220. Virbasius JV, Virbasius CA, and Scarpulla RC. Identity of GABP with NRF-2, a multisubunit activator of cytochrome oxidase expression, reveals a cellular role for an ETS domain activator of viral promoters. Genes Dev 7: 380-392, 1993
221. Vlashi E, Lagadec C, Vergnes L, Matsutani T, Masui K, Poulou M, Popescu R, Della Donna L, Evers P, Dekmezian C, Reue K, Christofk H, Mischel PS, and Pajonk F. Metabolic state of glioma stem cells and nontumorigenic cells. Proc Natl Acad Sci USA 108: 16062-16067, 2011
222. Vlashi E, Lagadec C, Vergnes L, Reue K, Frohnen P, Chan M, Alhiyari Y, Dratver MB, and Pajonk F. Metabolic differences in breast cancer stem cells and differentiated progeny. Breast Cancer Res Treat 146: 525-534, 2014
223. Wallace C and Keast D. Glutamine and macrophage function. Metabolism 41: 1016-1020, 1992
224. Wallace DC. Mitochondrial diseases in man and mouse. Science 283: 1482-1488, 1999
225. Wang C, Li Z, Lu Y, Du R, Katiyar S, Yang J, Fu M, Leader JE, Quong A, Novikoff PM, and Pestell RG. Cyclin D1 repression of nuclear respiratory factor 1 integrates nuclear DNA synthesis and mitochondrial function. Proc Natl Acad Sci USA 103: 11567-11572, 2006
226. Wang J, Ying G, Wang J, Jung Y, Lu J, Zhu J, Pienta KJ, and Taichman RS. Characterization of phosphoglycerate kinase-1 expression of stromal cells derived from tumor microenvironment in prostate cancer progression. Cancer Res 70: 471-480, 2010
227. Wang Z, Fan M, Candas D, Zhang TQ, Qin L, Eldridge A, Wachsmann-Hogiu S, Ahmed KM, Chromy BA, Nantajit D, Duru N, He F, Chen M, Finkel T, Weinstein LS, and Li JJ. Cyclin B1/Cdk1 coordinates mitochondrial respiration for cell-cycle G2/M progression. Dev Cell 29: 217-232, 2014
228. Warburg O. On respiratory impairment in cancer cells. Science 124: 269-270, 1956
229. Warburg O, Wind, F. and Negelein, E. The metabolism of tumors in the body. J Gener Physiol 8: 519-530, 1927
230. Ward PS, Patel J, Wise DR, Abdel-Wahab O, Bennett BD, Coller HA, Cross JR, Fantin VR, Hedvat CV, Perl AE, Rabinowitz JD, Carroll M, Su SM, Sharp KA, Levine RL, and Thompson CB. The common feature of leukemiaassociated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. Cancer Cell 17: 225-234, 2010
231. Ward PS and Thompson CB. Metabolic reprogramming: a cancer hallmark even warburg did not anticipate. Cancer Cell 21: 297-308, 2012
232. Watkins G, Douglas-Jones A, Mansel RE, and Jiang WG. The localisation and reduction of nuclear staining of PPARgamma and PGC-1 in human breast cancer. Oncol Rep 12: 483-488, 2004
233. Weinert BT, Wagner SA, Horn H, Henriksen P, Liu WR, Olsen JV, Jensen LJ, and Choudhary C. Proteome-wide mapping of the Drosophila acetylome demonstrates a high degree of conservation of lysine acetylation. Sci Signal 4: ra48, 2011
234. Weinhouse S. On respiratory impairment in cancer cells. Science 124: 267-269, 1956
235. Weinhouse S. Oxidative metabolism of neoplastic tissues. Adv Cancer Res 3: 269-325, 1955
236. Weinhouse S. The Warburg hypothesis fifty years later. Z Krebsforsch klin Onkol Cancer Res Clin Oncol 87: 115-126, 1976
237. Wellen KE, Hatzivassiliou G, Sachdeva UM, Bui TV, Cross JR, and Thompson CB. ATP-citrate lyase links cellular metabolism to histone acetylation. Science 324: 1076-1080, 2009
238. Wellen KE and Thompson CB. A two-way street: reciprocal regulation of metabolism and signalling. Nat Rev Mol Cell Biol 13: 270-276, 2012
239. Wenner CE, Spirtes MA, and Weinhouse S. Metabolism of neoplastic tissue. II. A survey of enzymes of the citric acid cycle in transplanted tumors. Cancer Res 12: 44-49, 1952
240. Weraarpachai W, Antonicka H, Sasarman F, Seeger J, Schrank B, Kolesar JE, Lochmuller H, Chevrette M, Kaufman BA, Horvath R, and Shoubridge EA. Mutation in TACO1, encoding a translational activator of COX I, results in cytochrome c oxidase deficiency and late-onset Leigh syndrome. Nat Genet 41: 833-837, 2009
241. Wise DR, DeBerardinis RJ, Mancuso A, Sayed N, Zhang XY, Pfeiffer HK, Nissim I, Daikhin E, Yudkoff M, McMahon SB, and Thompson CB. Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction. Proc Natl Acad Sci USA 105: 18782-18787, 2008
242. Wright G, Terada K, Yano M, Sergeev I, and Mori M. Oxidative stress inhibits the mitochondrial import of preproteins and leads to their degradation. Exp Cell Res 263: 107-117, 2001
243. Yang L, Moss T, Mangala LS, Marini J, Zhao H, Wahlig S, Armaiz-Pena G, Jiang D, Achreja A, Win J, Roopaimoole R, Rodriguez-Aguayo C, Mercado-Uribe I, Lopez-Berestein G, Liu J, Tsukamoto T, Sood AK, Ram PT, and Nagrath D. Metabolic shifts toward glutamine regulate tumor growth, invasion and bioenergetics in ovarian cancer. Mol Syst Biol 10: 728, 2014
244. Yao P and Fox PL. Aminoacyl-tRNA synthetases in medicine and disease. EMBO Mol Med 5: 332-343, 2013
245. Ye J, Mancuso A, Tong X, Ward PS, Fan J, Rabinowitz JD, and Thompson CB. Pyruvate kinase M2 promotes de novo serine synthesis to sustain mTORC1 activity and cell proliferation. Proc Natl Acad Sci USA 109: 6904-6909, 2012
246. Ye XQ, Li Q, Wang GH, Sun FF, Huang GJ, Bian XW, Yu SC, and Qian GS. Mitochondrial and energy metabolism-related properties as novel indicators of lung cancer stem cells. Int J Cancer 129: 820-831, 2011
247. Yu Q, Geng Y, and Sicinski P. Specific protection against breast cancers by cyclin D1 ablation. Nature 411: 1017-1021, 2001
248. Yuan Y, Gu ZX, Tao XF, and Liu SY. Computer tomography, magnetic resonance imaging, and positron emission tomography or positron emission tomography/ computer tomography for detection of metastatic lymph nodes in patients with ovarian cancer: a meta-analysis. Eur J Radiol 81: 1002-1006, 2012
249. Yuneva M, Zamboni N, Oefner P, Sachidanandam R, and Lazebnik Y. Deficiency in glutamine but not glucose induces MYC-dependent apoptosis in human cells. J Cell Biol 178: 93-105, 2007
250. Zhang D, Wang Y, Shi Z, Liu J, Sun P, Hou X, Zhang J, Zhao S, Zhou BP, and Mi J. Metabolic reprogramming of cancer-associated fibroblasts by IDH3alpha downregulation. Cell Rep 10: 1335-1348, 2015
251. Zhang Y, Ba Y, Liu C, Sun G, Ding L, Gao S, Hao J, Yu Z, Zhang J, Zen K, Tong Z, Xiang Y, and Zhang CY. PGC-1alpha induces apoptosis in human epithelial ovarian cancer cells through a PPARgamma-dependent pathway. Cell Res 17: 363-373, 2007
252. Zhang Y, Choksi S, Chen K, Pobezinskaya Y, Linnoila I, and Liu ZG. ROS play a critical role in the differentiation of alternatively activated macrophages and the occurrence of tumor-associated macrophages. Cell Res 23: 898-914, 2013
253. Zu XL and Guppy M. Cancer metabolism: facts, fantasy, and fiction. Biochem Biophys Res Commun 313: 459-465, 2004