Regulation of T cell immunity by cellular metabolism

Abstract

T cells are an important adaptive immune response arm that mediates cell-mediated immunity. T cell metabolism plays a central role in T cell activation, proliferation, differentiation, and effector function. Specific metabolic programs are tightly controlled to mediate T cell immune responses, and alterations in T cell metabolism may result in many immunological disorders. In this review, we will summarize the main T cell metabolic pathways and the important factors participating in T cell metabolic programming during T cell homeostasis, differentiation, and function.

Keywords

T cell immunity / metabolic pathways / nutrient uptake / metabolic checkpoints

References

[1] Segal BH. Role of macrophages in host defense against aspergillosis and strategies for immune augmentation. Oncologist 2007; 12(Suppl 2): 7–13

[2] Harwood CG, Rao RP. Host pathogen relations: exploring animal models for fungal pathogens. Pathogens 2014; 3(3): 549–562

[3] Ron-Harel N, Sharpe AH, Haigis MC. Mitochondrial metabolism in T cell activation and senescence: a mini-review. Gerontology 2015; 61(2): 131–138

[4] Pearce EL, Pearce EJ. Metabolic pathways in immune cell activation and quiescence. Immunity 2013; 38(4): 633–643

[5] Pennock ND, White JT, Cross EW, Cheney EE, Tamburini BA, Kedl RM. T cell responses: naïve to memory and everything in between. Adv Physiol Educ 2013; 37(4): 273–283

[6] Lauvau G, Soudja SM. Mechanisms of Memory T Cell Activation and Effective Immunity. Crossroads, between Innate and Adaptive Immunity. Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 850). 2015; 850: 73–80

[7] Brenchley JM, Douek DC, Ambrozak DR, Chatterji M, Betts MR, Davis LS, Koup RA. Expansion of activated human naïve T-cells precedes effector function. Clin Exp Immunol 2002; 130(3): 432–440

[8] Zhang N, Hartig H, Dzhagalov I, Draper D, He YW. The role of apoptosis in the development and function of T lymphocytes. Cell Res 2005; 15(10): 749–769

[9] Schumacher TN, Gerlach C, van Heijst JW. Mapping the life histories of T cells. Nat Rev Immunol 2010; 10(9): 621–631

[10] Wang R, Green DR. Metabolic checkpoints in activated T cells. Nat Immunol 2012; 13(10): 907–915

[11] Ray JP, Staron MM, Shyer JA, Ho PC, Marshall HD, Gray SM, Laidlaw BJ, Araki K, Ahmed R, Kaech SM, Craft J. The interleukin-2-mTORc1 kinase axis defines the signaling, differentiation, and metabolism of T helper 1 and follicular B helper T cells. Immunity 2015; 43(4): 690–702

[12] Wu T, Shin HM, Moseman EA, Ji Y, Huang B, Harly C, Sen JM, Berg LJ, Gattinoni L, McGavern DB, Schwartzberg PL. TCF1 is required for the T follicular helper cell response to viral infection. Cell Reports 2015; 12(12): 2099–2110

[13] Johnston RJ, Poholek AC, DiToro D, Yusuf I, Eto D, Barnett B, Dent AL, Craft J, Crotty S. Bcl6 and Blimp-1 are reciprocal and antagonistic regulators of T follicular helper cell differentiation. Science 2009; 325(5943): 1006–1010

[14] Nurieva RI, Chung Y, Martinez GJ, Yang XO, Tanaka S, Matskevitch TD, Wang YH, Dong C. Bcl6 mediates the development of T follicular helper cells. Science 2009; 325(5943): 1001–1005

[15] Oestreich KJ, Read KA, Gilbertson SE, Hough KP, McDonald PW, Krishnamoorthy V, Weinmann AS. Bcl-6 directly represses the gene program of the glycolysis pathway. Nat Immunol 2014; 15(10): 957–964

[16] Oestreich KJ, Mohn SE, Weinmann AS. Molecular mechanisms that control the expression and activity of Bcl-6 in TH1 cells to regulate flexibility with a TFH-like gene profile. Nat Immunol 2012; 13(4): 405–411

[17] Scharping NE, Menk AV, Moreci RS, Whetstone RD, Dadey RE, Watkins SC, Ferris RL, Delgoffe GM. The tumor microenvironment represses T cell mitochondrial biogenesis to drive intratumoral T cell metabolic insufficiency and dysfunction. Immunity 2016; 45(3): 701–703

[18] Bengsch B, Johnson AL, Kurachi M, Odorizzi PM, Pauken KE, Attanasio J, Stelekati E, McLane LM, Paley MA, Delgoffe GM, Wherry EJ. Bioenergetic insufficiencies due to metabolic alterations regulated by the inhibitory receptor PD-1 are an early driver of CD8⁺ T cell exhaustion. Immunity 2016; 45(2): 358–373

[19] Austin S, St-Pierre J. PGC1a and mitochondrial metabolism—emerging concepts and relevance in ageing and neurodegenerative disorders. J Cell Sci 2012; 125(Pt 21): 4963–4971

[20] Siska PJ, van der Windt GJ, Kishton RJ, Cohen S, Eisner W, MacIver NJ, Kater AP, Weinberg JB, Rathmell JC. Suppression of Glut1 and glucose metabolism by decreased Akt/mTORC1 signaling drives T cell impairment in B cell leukemia. J Immunol 2016; 197(6): 2532–2540

[21] Fox CJ, Hammerman PS, Thompson CB. Fuel feeds function: energy metabolism and the T-cell response. Nat Rev Immunol 2005; 5(11): 844–852

[22] Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 2009; 324(5930): 1029–1033

[23] Wahl DR, Byersdorfer CA, Ferrara JL, Opipari AW Jr, Glick GD. Distinct metabolic programs in activated T cells: opportunities for selective immunomodulation. Immunol Rev 2012; 249(1): 104–115

[24] De Boer RJ, Homann D, Perelson AS. Different dynamics of CD4⁺ and CD8⁺ T cell responses during and after acute lymphocytic choriomeningitis virus infection. J Immunol 2003; 171(8): 3928–3935

[25] Pearce EL, Walsh MC, Cejas PJ, Harms GM, Shen H, Wang LS, Jones RG, Choi Y. Enhancing CD8 T-cell memory by modulating fatty acid metabolism. Nature 2009; 460(7251): 103–107

[26] Schwenk RW, Holloway GP, Luiken JJ, Bonen A, Glatz JF. Fatty acid transport across the cell membrane: regulation by fatty acid transporters. Prostaglandins Leukot Essent Fatty Acids 2010; 82(4-6): 149–154

[27] Michalek RD, Gerriets VA, Jacobs SR, Macintyre AN, MacIver NJ, Mason EF, Sullivan SA, Nichols AG, Rathmell JC. Cutting edge: distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4⁺ T cell subsets. J Immunol 2011; 186(6): 3299–3303

[28] Delgoffe GM, Pollizzi KN, Waickman AT, Heikamp E, Meyers DJ, Horton MR, Xiao B, Worley PF, Powell JD. The kinase mTOR regulates the differentiation of helper T cells through the selective activation of signaling by mTORC1 and mTORC2. Nat Immunol 2011; 12(4): 295–303

[29] van der Windt GJ, Everts B, Chang CH, Curtis JD, Freitas TC, Amiel E, Pearce EJ, Pearce EL. Mitochondrial respiratory capacity is a critical regulator of CD8⁺ T cell memory development. Immunity 2012; 36(1): 68–78

[30] Lochner M, Berod L, Sparwasser T. Fatty acid metabolism in the regulation of T cell function. Trends Immunol 2015; 36(2): 81–91

[31] Fraser KA, Schenkel JM, Jameson SC, Vezys V, Masopust D. Preexisting high frequencies of memory CD8⁺ T cells favor rapid memory differentiation and preservation of proliferative potential upon boosting. Immunity 2013; 39(1): 171–183

[32] van der Windt GJ, O’Sullivan D, Everts B, Huang SC, Buck MD, Curtis JD, Chang CH, Smith AM, Ai T, Faubert B, Jones RG, Pearce EJ, Pearce EL. CD8 memory T cells have a bioenergetic advantage that underlies their rapid recall ability. Proc Natl Acad Sci USA 2013; 110(35): 14336–14341

[33] Nicholls DG. Spare respiratory capacity, oxidative stress and excitotoxicity. Biochem Soc Trans 2009; 37(Pt 6): 1385–1388

[34] Newsholme EA, Crabtree B, Ardawi MS. The role of high rates of glycolysis and glutamine utilization in rapidly dividing cells. Biosci Rep 1985; 5(5): 393–400

[35] van Stipdonk MJ, Hardenberg G, Bijker MS, Lemmens EE, Droin NM, Green DR, Schoenberger SP. Dynamic programming of CD8⁺ T lymphocyte responses. Nat Immunol 2003; 4(4): 361–365

[36] Rathmell JC, Vander Heiden MG, Harris MH, Frauwirth KA, Thompson CB. In the absence of extrinsic signals, nutrient utilization by lymphocytes is insufficient to maintain either cell size or viability. Mol Cell 2000; 6(3): 683–692

[37] Mueckler M, Thorens B. The SLC2 (GLUT) family of membrane transporters. Mol Aspects Med 2013; 34(2-3): 121–138

[38] Scheepers A, Joost HG, Schürmann A. The glucose transporter families SGLT and GLUT: molecular basis of normal and aberrant function. JPEN J Parenter Enteral Nutr 2004; 28(5): 364–371

[39] Wood IS, Trayhurn P. Glucose transporters (GLUT and SGLT): expanded families of sugar transport proteins. Br J Nutr 2003; 89(1): 3–9

[40] Macintyre AN, Gerriets VA, Nichols AG, Michalek RD, Rudolph MC, Deoliveira D, Anderson SM, Abel ED, Chen BJ, Hale LP, Rathmell JC. The glucose transporter Glut1 is selectively essential for CD4 T cell activation and effector function. Cell Metab 2014; 20(1): 61–72

[41] Qu Q, Zeng F, Liu X, Wang QJ, Deng F. Fatty acid oxidation and carnitine palmitoyltransferase I: emerging therapeutic targets in cancer. Cell Death Dis 2016; 7(5): e2226

[42] Chakrabarti R, Jung CY, Lee TP, Liu H, Mookerjee BK. Changes in glucose transport and transporter isoforms during the activation of human peripheral blood lymphocytes by phytohemagglutinin. J Immunol 1994; 152(6): 2660–2668

[43] Frauwirth KA, Riley JL, Harris MH, Parry RV, Rathmell JC, Plas DR, Elstrom RL, June CH, Thompson CB. The CD28 signaling pathway regulates glucose metabolism. Immunity 2002; 16(6): 769–777

[44] Jacobs SR, Herman CE, Maciver NJ, Wofford JA, Wieman HL, Hammen JJ, Rathmell JC. Glucose uptake is limiting in T cell activation and requires CD28-mediated Akt-dependent and independent pathways. J Immunol 2008; 180(7): 4476–4486

[45] Nakaya M, Xiao Y, Zhou X, Chang JH, Chang M, Cheng X, Blonska M, Lin X, Sun SC. Inflammatory T cell responses rely on amino acid transporter ASCT2 facilitation of glutamine uptake and mTORC1 kinase activation. Immunity 2014; 40(5): 692–705

[46] Sinclair LV, Rolf J, Emslie E, Shi YB, Taylor PM, Cantrell DA. Control of amino-acid transport by antigen receptors coordinates the metabolic reprogramming essential for T cell differentiation. Nat Immunol 2013; 14(5): 500–508

[47] Verrey F, Closs EI, Wagner CA, Palacin M, Endou H, Kanai Y. CATs and HATs: the SLC7 family of amino acid transporters. Pflugers Arch 2004; 447(5): 532–542

[48] Hayashi K, Jutabha P, Endou H, Sagara H, Anzai N. LAT1 is a critical transporter of essential amino acids for immune reactions in activated human T cells. J Immunol 2013; 191(8): 4080–4085

[49] Pearce EL, Walsh MC, Cejas PJ, Harms GM, Shen H, Wang LS, Jones RG, Choi Y. Enhancing CD8 T-cell memory by modulating fatty acid metabolism. Nature 2009; 460(7251): 103–107

[50] Rao RR, Li Q, Odunsi K, 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 2010; 32(1): 67–78

[51] Araki K, Turner AP, Shaffer VO, Gangappa S, Keller SA, Bachmann MF, Larsen CP, Ahmed R. mTOR regulates memory CD8 T-cell differentiation. Nature 2009; 460(7251): 108–112

[52] Brown EJ, Albers MW, Shin TB, Ichikawa K, Keith CT, Lane WS, Schreiber SL. A mammalian protein targeted by G1-arresting rapamycin-receptor complex. Nature 1994; 369(6483): 756–758

[53] Delgoffe GM, Kole TP, Zheng Y, Zarek PE, Matthews KL, Xiao B, Worley PF, Kozma SC, Powell JD. The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment. Immunity 2009; 30(6): 832–844

[54] Battaglia M, Stabilini A, Migliavacca B, Horejs-Hoeck J, Kaupper T, Roncarolo MG. Rapamycin promotes expansion of functional CD4⁺CD25⁺FOXP3⁺ regulatory T cells of both healthy subjects and type 1 diabetic patients. J Immunol 2006; 177(12): 8338–8347

[55] Battaglia M, Stabilini A, Roncarolo MG. Rapamycin selectively expands CD4⁺CD25⁺FoxP3⁺ regulatory T cells. Blood 2005; 105(12): 4743–4748

[56] Kurebayashi Y, Nagai S, Ikejiri A, Ohtani M, Ichiyama K, Baba Y, Yamada T, Egami S, Hoshii T, Hirao A, Matsuda S, Koyasu S. PI3K-Akt-mTORC1-S6K1/2 axis controls Th17 differentiation by regulating Gfi1 expression and nuclear translocation of RORg. Cell Reports 2012; 1(4): 360–373

[57] Wu X, Dou Y, Yang Y, Bian D, Luo J, Tong B, Xia Y, Dai Y. Arctigenin exerts anti-colitis efficacy through inhibiting the differentiation of Th1 and Th17 cells via an mTORC1-dependent pathway. Biochem Pharmacol 2015; 96(4): 323–336

[58] Yang K, Shrestha S, Zeng H, Karmaus PW, Neale G, Vogel P, Guertin DA, Lamb RF, Chi H. T cell exit from quiescence and differentiation into Th2 cells depend on Raptor-mTORC1-mediated metabolic reprogramming. Immunity 2013; 39(6): 1043–1056

[59] Lee K, Gudapati P, Dragovic S, Spencer C, Joyce S, Killeen N, Magnuson MA, Boothby M. Mammalian target of rapamycin protein complex 2 regulates differentiation of Th1 and Th2 cell subsets via distinct signaling pathways. Immunity 2010; 32(6): 743–753

[60] Buller CL, Loberg RD, Fan MH, Zhu Q, Park JL, Vesely E, Inoki K, Guan KL, Brosius FC 3rd. A GSK-3/TSC2/mTOR pathway regulates glucose uptake and GLUT1 glucose transporter expression. Am J Physiol Cell Physiol 2008; 295(3): C836–C843

[61] Gerriets VA, Kishton RJ, Nichols AG, Macintyre AN, Inoue M, Ilkayeva O, Winter PS, Liu X, Priyadharshini B, Slawinska ME, Haeberli L, Huck C, Turka LA, Wood KC, Hale LP, Smith PA, Schneider MA, MacIver NJ, Locasale JW, Newgard CB, Shinohara ML, Rathmell JC. Metabolic programming and PDHK1 control CD4⁺ T cell subsets and inflammation. J Clin Invest 2015; 125(1): 194–207

[62] Hadis U, Wahl B, Schulz O, Hardtke-Wolenski M, Schippers A, Wagner N, Müller W, Sparwasser T, Förster R, Pabst O. Intestinal tolerance requires gut homing and expansion of FoxP3⁺ regulatory T cells in the lamina propria. Immunity 2011; 34(2): 237–246

[63] Shi LZ, Wang R, Huang G, Vogel P, Neale G, Green DR, Chi H. HIF1α-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells. J Exp Med 2011; 208(7): 1367–1376

[64] Zeng H, Yang K, Cloer C, Neale G, Vogel P, Chi H. mTORC1 couples immune signals and metabolic programming to establish T(reg)-cell function. Nature 2013; 499(7459): 485–490

[65] Hardie DG, Scott JW, Pan DA, Hudson ER. Management of cellular energy by the AMP-activated protein kinase system. FEBS Lett 2003; 546(1): 113–120

[66] Hardie DG. Minireview: the AMP-activated protein kinase cascade: the key sensor of cellular energy status. Endocrinology 2003; 144(12): 5179–5183

[67] Tamás P, Hawley SA, Clarke RG, Mustard KJ, Green K, Hardie DG, Cantrell DA. Regulation of the energy sensor AMP-activated protein kinase by antigen receptor and Ca²⁺ in T lymphocytes. J Exp Med 2006; 203(7): 1665–1670

[68] Xu J, Ji J, Yan XH. Cross-talk between AMPK and mTOR in regulating energy balance. Crit Rev Food Sci Nutr 2012; 52(5): 373–381

[69] Zhao D, Long XD, Lu TF, Wang T, Zhang WW, Liu YX, Cui XL, Dai HJ, Xue F, Xia Q. Metformin decreases IL-22 secretion to suppress tumor growth in an orthotopic mouse model of hepatocellular carcinoma. Int J Cancer 2015; 136(11): 2556–2565

[70] Kang KY, Kim YK, Yi H, Kim J, Jung HR, Kim IJ, Cho JH, Park SH, Kim HY, Ju JH. Metformin downregulates Th17 cells differentiation and attenuates murine autoimmune arthritis. Int Immunopharmacol 2013; 16(1): 85–92

[71] Bai A, Yong M, Ma AG, Ma Y, Weiss CR, Guan Q, Bernstein CN, Peng Z. Novel anti-inflammatory action of 5-aminoimidazole-4-carboxamide ribonucleoside with protective effect in dextran sulfate sodium-induced acute and chronic colitis. J Pharmacol Exp Ther 2010; 333(3): 717–725

[72] Son HJ, Lee J, Lee SY, Kim EK, Park MJ, Kim KW, Park SH, Cho ML. Metformin attenuates experimental autoimmune arthritis through reciprocal regulation of Th17/Treg balance and osteoclastogenesis. Mediators Inflamm 2014; 2014: 973986

[73] Lee SY, Lee SH, Yang EJ, Kim EK, Kim JK, Shin DY, Cho ML. Metformin ameliorates inflammatory bowel disease by suppression of the STAT3 signaling pathway and regulation of the between Th17/Treg balance. PLoS One 2015; 10(9): e0135858

[74] Bai A, Ma AG, Yong M, Weiss CR, Ma Y, Guan Q, Bernstein CN, Peng Z. AMPK agonist downregulates innate and adaptive immune responses in TNBS-induced murine acute and relapsing colitis. Biochem Pharmacol 2010; 80(11): 1708–1717

[75] Nath N, Giri S, Prasad R, Salem ML, Singh AK, Singh I. 5-aminoimidazole-4-carboxamide ribonucleoside: a novel immunomodulator with therapeutic efficacy in experimental autoimmune encephalomyelitis. J Immunol 2005; 175(1): 566–574

[76] Boxer LM, Dang CV. Translocations involving c-myc and c-myc function. Oncogene 2001; 20(40): 5595–5610

[77] Erikson J, ar-Rushdi A, Drwinga HL, Nowell PC, Croce CM. Transcriptional activation of the translocated c-myc oncogene in burkitt lymphoma. Proc Natl Acad Sci USA 1983; 80(3): 820–824

[78] Wang R, Dillon CP, Shi LZ, Milasta S, Carter R, Finkelstein D, McCormick LL, Fitzgerald P, Chi H, Munger J, Green DR. The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation. Immunity 2011; 35(6): 871–882

[79] Sinclair LV, Rolf J, Emslie E, Shi YB, Taylor PM, Cantrell DA. Control of amino-acid transport by antigen receptors coordinates the metabolic reprogramming essential for T cell differentiation. Nat Immunol 2013; 14(5): 500–508

[80] Molon B, Calì B, Viola A. T cells and cancer: how metabolism shapes immunity. Front Immunol 2016; 7: 20

[81] Frey AB. Suppression of T cell responses in the tumor microenvironment. Vaccine 2015; 33(51): 7393–7400

[82] Vinay DS, Ryan EP, Pawelec G, Talib WH, Stagg J, Elkord E, Lichtor T, Decker WK, Whelan RL, Kumara HMCS, Signori E, Honoki K, Georgakilas AG, Amin A, Helferich WG, Boosani CS, Guha G, Ciriolo MR, Chen S, Mohammed SI, Azmi AS, Keith WN, Bilsland A, Bhakta D, Halicka D, Fujii H, Aquilano K, Ashraf SS, Nowsheen S, Yang X, Choi BK, Kwon BS. Immune evasion in cancer: mechanistic basis and therapeutic strategies. Semin Cancer Biol 2015; 35(Suppl): S185–S198

[83] Kim R, Emi M, Tanabe K. Cancer immunoediting from immune surveillance to immune escape. Immunology 2007; 121(1): 1–14

[84] Gajewski TF, Fuertes M, Spaapen R, Zheng Y, Kline J. Molecular profiling to identify relevant immune resistance mechanisms in the tumor microenvironment. Curr Opin Immunol 2011; 23(2): 286–292

[85] Bianchi G, Borgonovo G, Pistoia V, Raffaghello L. Immunosuppressive cells and tumour microenvironment: focus on mesenchymal stem cells and myeloid derived suppressor cells. Histol Histopathol 2011; 26(7): 941–951

[86] Taylor ES, McCall JL, Girardin A, Munro FM, Black MA, Kemp RA. Functional impairment of infiltrating T cells in human colorectal cancer. OncoImmunology 2016; 5(11): e1234573

[87] Quail DF, Joyce JA. Microenvironmental regulation of tumor progression and metastasis. Nat Med 2013; 19(11): 1423–1437

[88] Herbel C, Patsoukis N, Bardhan K, Seth P, Weaver JD, Boussiotis VA. Clinical significance of T cell metabolic reprogramming in cancer. Clin Transl Med 2016; 5(1): 29

[89] 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, Pearce EL. Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell 2015; 162(6): 1229–1241

[90] Zhang Y, Ertl HC. Starved and asphyxiated: how can CD8⁺ T cells within a tumor microenvironment prevent tumor progression. Front Immunol 2016; 7: 32

[91] Nakaigawa N, Kondo K, Ueno D, Namura K, Makiyama K, Kobayashi K, Shioi K, Ikeda I, Kishida T, Kaneta T, Minamimoto R, Tateishi U, Inoue T, Yao M. The acceleration of glucose accumulation in renal cell carcinoma assessed by FDG PET/CT demonstrated acquisition of resistance to tyrosine kinase inhibitor therapy. BMC Cancer 2017; 17(1): 39

[92] Crespo J, Sun H, Welling TH, Tian Z, Zou W. T cell anergy, exhaustion, senescence, and stemness in the tumor microenvironment. Curr Opin Immunol 2013; 25(2): 214–221

[93] Chaudhary B, Elkord E. Regulatory T cells in the tumor microenvironment and cancer progression: role and therapeutic targeting. Vaccines (Basel) 2016; 4(3): E28

[94] Yaqub S, Henjum K, Mahic M, Jahnsen FL, Aandahl EM, Bjørnbeth BA, Taskén K. Regulatory T cells in colorectal cancer patients suppress anti-tumor immune activity in a COX-2 dependent manner. Cancer Immunol Immunother 2008; 57(6): 813–821

[95] Chaudhary B, Abd Al Samid M, al-Ramadi BK, Elkord E. Phenotypic alterations, clinical impact and therapeutic potential of regulatory T cells in cancer. Expert Opin Biol Ther 2014; 14(7): 931–945

[96] Chi H. Regulation and function of mTOR signalling in T cell fate decisions. Nat Rev Immunol 2012; 12(5): 325–338

[97] Chaube B, Bhat MK. AMPK, a key regulator of metabolic/energy homeostasis and mitochondrial biogenesis in cancer cells. Cell Death Dis 2016; 7(1): e2044

Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (Nos. 81430033, 31470845, and 31670896), the Recruitment Program of Global Experts of China, Shanghai Rising-Star Program (No. 16QA1403300), Shanghai Science and Technology Committee (No. 16410723300), Shanghai Municipal Commission of Health and Family Planning (Nos. 20174Y0049, 20174Y0191, and 15GWZK0102), Shanghai Jiao Tong University “Program for young teachers” (No. KJ30214170006) and “Medical and Engineering Cross Research Foundation” (No. YG2016QN77).

Compliance with ethics guidelines

Zhilin Hu, Qiang Zou, and Bing Su declare no conflict of interest. This manuscript is a review article and does not involve a research protocol requiring approval by the relevant institutional review board or ethics committee.

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