PKM2 coordinates glycolysis with mitochondrial fusion and oxidative phosphorylation

doi:10.1007/s13238-019-0618-z

Protein Cell

2019, Vol. 10

Issue (8) : 583-594 https://doi.org/10.1007/s13238-019-0618-z

RESEARCH ARTICLE

PKM2 coordinates glycolysis with mitochondrial fusion and oxidative phosphorylation

Tong Li, Jinbo Han, Liangjie Jia, Xiao Hu, Liqun Chen, Yiguo Wang(

)

MOE Key Laboratory of Bioinformatics, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China

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Abstract

A change in the metabolic flux of glucose from mitochondrial oxidative phosphorylation (OXPHOS) to aerobic glycolysis is regarded as one hallmark of cancer. However, the mechanisms underlying the metabolic switch between aerobic glycolysis and OXPHOS are unclear. Here we show that the M2 isoform of pyruvate kinase (PKM2), one of the rate-limiting enzymes in glycolysis, interacts with mitofusin 2 (MFN2), a key regulator of mitochondrial fusion, to promote mitochondrial fusion and OXPHOS, and attenuate glycolysis. mTOR increases the PKM2:MFN2 interaction by phosphorylating MFN2 and thereby modulates the effect of PKM2: MFN2 on glycolysis, mitochondrial fusion and OXPHOS. Thus, an mTOR-MFN2-PKM2 signaling axis couples glycolysis and OXPHOS to modulate cancer cell growth.

Keywords PKM2 MFN2 mTOR glycolysis oxidative phosphorylation

Corresponding Author(s): Yiguo Wang

Issue Date: 22 August 2019

Cite this article:

Tong Li,Jinbo Han,Liangjie Jia, et al. PKM2 coordinates glycolysis with mitochondrial fusion and oxidative phosphorylation[J]. Protein Cell, 2019, 10(8): 583-594.

URL:

https://academic.hep.com.cn/pac/EN/10.1007/s13238-019-0618-z
https://academic.hep.com.cn/pac/EN/Y2019/V10/I8/583

1	D Anastasiou, Y Yu, WJ Israelsen, JK Jiang, MB Boxer, BS Hong, W Tempel, S Dimov, M Shen, A Jhaet al. (2012) Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis. Nat Chem Biol 8:839–847 https://doi.org/10.1038/nchembio.1060
2	MD Buck, D O’Sullivan, RI Klein Geltink, JD Curtis, CH Chang, DE Sanin, J Qiu, O Kretz, D Braas, GJ van der Windtet al. (2016) Mitochondrial dynamics controls T cell fate through metabolic programming. Cell 166:63–76 https://doi.org/10.1016/j.cell.2016.05.035
3	B Chaneton, P Hillmann, L Zheng, ACL Martin, ODK Maddocks, A Chokkathukalam, JE Coyle, A Jankevics, FP Holding, KH Vousdenet al. (2012) Serine is a natural ligand and allosteric activator of pyruvate kinase M2. Nature 491:458–462 https://doi.org/10.1038/nature11540
4	H Chen, DC Chan (2017) Mitochondrial dynamics in regulating the unique phenotypes of cancer and stem cells. Cell Metab 26:39–48 https://doi.org/10.1016/j.cmet.2017.05.016
5	Y Chen, GW Dorn 2nd (2013) PINK1-phosphorylated mitofusin 2 is a Parkin receptor for culling damaged mitochondria. Science 340:471–475 https://doi.org/10.1126/science.1231031
6	H Chen, A Chomyn, DC Chan (2005) Disruption of fusion results in mitochondrial heterogeneity and dysfunction. J Biol Chem 280:26185–26192 https://doi.org/10.1074/jbc.M503062200
7	L Chen, K Wang, A Long, L Jia, Y Zhang, H Deng, Y Li, J Han, Y Wang (2017) Fasting-induced hormonal regulation of lysosomal function. Cell Res 27:748–763 https://doi.org/10.1038/cr.2017.45
8	HR Christofk, MG Vander Heiden, MH Harris, A Ramanathan, RE Gerszten, R Wei, MD Fleming, SL Schreiber, LC Cantley (2008a) The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature 452:230–233 https://doi.org/10.1038/nature06734
9	HR Christofk, MG Vander Heiden, N Wu, JM Asara, LC Cantley (2008b) Pyruvate kinase M2 is a phosphotyrosine-binding protein. Nature 452:181–186 https://doi.org/10.1038/nature06667
10	M Cornu, V Albert, MN Hall (2013) mTOR in aging, metabolism, and cancer. Curr Opin Genet Dev 23:53–62 https://doi.org/10.1016/j.gde.2012.12.005
11	TL Dayton, T Jacks, MG Vander Heiden (2016) PKM2, cancer metabolism, and the road ahead. EMBO Rep 17:1721–1730 https://doi.org/10.15252/embr.201643300
12	VR Fantin, J St-Pierre, P Leder (2006) Attenuation of LDH-A expression uncovers a link between glycolysis, mitochondrial physiology, and tumor maintenance. Cancer Cell 9:425–434 https://doi.org/10.1016/j.ccr.2006.04.023
13	D Garcia, RJ Shaw (2017) AMPK: mechanisms of cellular energy sensing and restoration of metabolic balance. Mol Cell 66:789–800 https://doi.org/10.1016/j.molcel.2017.05.032
14	V Gogvadze, S Orrenius, B Zhivotovsky (2008) Mitochondria in cancer cells: what is so special about them? Trends Cell Biol 18:165–173 https://doi.org/10.1016/j.tcb.2008.01.006
15	G Gong, M Song, G Csordas, DP Kelly, SJ Matkovich, GW Dorn 2nd (2015) Parkin-mediated mitophagy directs perinatal cardiac metabolic maturation in mice. Science 350:aad2459 https://doi.org/10.1126/science.aad2459
16	J, Han E Li, L Chen, Y Zhang, F Wei, J Liu, H Deng, Y Wang (2015) The CREB coactivator CRTC2 controls hepatic lipid metabolism by regulating SREBP1. Nature 524:243–246 https://doi.org/10.1038/nature14557
17	D Hanahan, RA Weinberg (2011) Hallmarks of cancer: the next generation. Cell 144:646–674 https://doi.org/10.1016/j.cell.2011.02.013
18	PP Hsu, SA Kang, J Rameseder, Y Zhang, KA Ottina, D Lim, TR Peterson, Y, Choi NS Gray, MB Yaffeet al. (2011) The mTORregulated phosphoproteome reveals a mechanism of mTORC1-mediated inhibition of growth factor signaling. Science 332:1317–1322 https://doi.org/10.1126/science.1199498
19	WJ Israelsen, TL Dayton, SM Davidson, BP Fiske, AM Hosios, G Bellinger, J Li, Y Yu, M Sasaki, JW Horneret al. (2013) PKM2 isoform-specific deletion reveals a differential requirement for pyruvate kinase in tumor cells. Cell 155:397–409 https://doi.org/10.1016/j.cell.2013.09.025
20	KE Keller, IS Tan, YS Lee (2012) SAICAR stimulates pyruvate kinase isoform M2 and promotes cancer cell survival in glucoselimited conditions. Science 338:1069–1072 https://doi.org/10.1126/science.1224409
21	M Lazarou, DA Sliter, LA Kane, SA Sarraf, C Wang, JL Burman, DP Sideris, AI Fogel, RJ Youle (2015) The ubiquitin kinase PINK1 recruits autophagy receptors to induce mitophagy. Nature 524:309–314 https://doi.org/10.1038/nature14893
22	M Liesa, OS Shirihai (2013) Mitochondrial dynamics in the regulation of nutrient utilization and energy expenditure. Cell Metab 17:491–506 https://doi.org/10.1016/j.cmet.2013.03.002
23	P Mishra, DC Chan (2014) Mitochondrial dynamics and inheritance during cell division, development and disease. Nat Rev Mol Cell Biol 15:634–646 https://doi.org/10.1038/nrm3877
24	A Mourier, E Motori, T Brandt, M Lagouge, I Atanassov, A Galinier, G Rappl, S Brodesser, K Hultenby, C Dieterichet al.(2015) Mitofusin 2 is required to maintain mitochondrial coenzyme Q levels. J Cell Biol 208:429–442 https://doi.org/10.1083/jcb.201411100
25	J Rehman, HJ Zhang, PT Toth, Y Zhang, G Marsboom, Z Hong, R Salgia, AN Husain, C Wietholt, SL Archer (2012) Inhibition of mitochondrial fission prevents cell cycle progression in lung cancer. FASEB J 26:2175–2186 https://doi.org/10.1096/fj.11-196543
26	RA Saxton, DM Sabatini (2017) mTOR signaling in growth, metabolism, and disease. Cell 168:960–976 https://doi.org/10.1016/j.cell.2017.02.004
27	MN Serasinghe, SY Wieder, TT Renault, R Elkholi, JJ Asciolla, JL Yao, O Jabado, K Hoehn, Y Kageyama, H Sesakiet al. (2015) Mitochondrial division is requisite to RAS-induced transformation and targeted by oncogenic MAPK pathway inhibitors. Mol Cell 57:521–536 https://doi.org/10.1016/j.molcel.2015.01.003
28	Z Song, M Ghochani, JM McCaffery, TG Frey, DC Chan (2009) Mitofusins and OPA1 mediate sequential steps in mitochondrial membrane fusion. Mol Biol Cell 20:3525–3532 https://doi.org/10.1091/mbc.e09-03-0252
29	G Valentini, LR Chiarelli, R Fortin, M Dolzan, A Galizzi, DJ Abraham, C Wang, P Bianchi, A Zanella, A Mattevi (2002) Structure and function of human erythrocyte pyruvate kinase. Molecular basis of nonspherocytic hemolytic anemia. J Biol Chem 277:23807–23814 https://doi.org/10.1074/jbc.M202107200
30	MG Vander Heiden, RJ DeBerardinis (2017) Understanding the intersections between metabolism and cancer biology. Cell 168:657–669 https://doi.org/10.1016/j.cell.2016.12.039
31	MG, Vander Heiden LC Cantley, CB Thompson (2009) Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324:1029–1033 https://doi.org/10.1126/science.1160809
32	C Wang, LR Chiarelli, P Bianchi, DJ Abraham, A Galizzi, A Mattevi, A Zanella, G Valentini (2001) Human erythrocyte pyruvate kinase: characterization of the recombinant enzyme and a mutant form (R510Q) causing nonspherocytic hemolytic anemia. Blood 98:3113–3120 https://doi.org/10.1182/blood.V98.10.3113
33	W Yang, Z Lu (2015) Pyruvate kinase M2 at a glance. J Cell Sci 128:1655–1660 https://doi.org/10.1242/jcs.166629
34	RJ Youle, AM van der Bliek (2012) Mitochondrial fission, fusion, and stress. Science 337:1062–1065 https://doi.org/10.1126/science.1219855
35	CS Zhang, SA Hawley, Y Zong, M Li, Z Wang, A Gray, T Ma, J Cui, JW Feng, M Zhuet al. (2017) Fructose-1,6-bisphosphate and aldolase mediate glucose sensing by AMPK. Nature 548:112–116 https://doi.org/10.1038/nature23275
36	J Zhao, J Zhang, M Yu, Y Xie, Y Huang, DW Wolff, PW Abel, Y Tu (2013) Mitochondrial dynamics regulates migration and invasion of breast cancer cells. Oncogene 32:4814–4824 https://doi.org/10.1038/onc.2012.494

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