PKM2 coordinates glycolysis with mitochondrial fusion and oxidative phosphorylation

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.

Key words： PKM2; MFN2; mTOR; glycolysis; oxidative phosphorylation

References

1 Anastasiou D, Yu Y, Israelsen WJ, Jiang JK, Boxer MB, Hong BS, Tempel W, Dimov S, Shen M, Jha A (2012) Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis. Nat Chem Biol 8:839–847

2 Buck MD, O’Sullivan D, Klein Geltink RI, Curtis JD, Chang CH, Sanin DE, Qiu J, Kretz O, Braas D, van der Windt GJ (2016) Mitochondrial dynamics controls T cell fate through metabolic programming. Cell 166:63–76

3 Chaneton B, Hillmann P, Zheng L, Martin ACL, Maddocks ODK, Chokkathukalam A, Coyle JE, Jankevics A, Holding FP, Vousden KH (2012) Serine is a natural ligand and allosteric activator of pyruvate kinase M2. Nature 491:458–462

4 Chen H, Chan DC (2017) Mitochondrial dynamics in regulating the unique phenotypes of cancer and stem cells. Cell Metab 26:39–48

5 Chen Y, Dorn GW 2nd (2013) PINK1-phosphorylated mitofusin 2 is a Parkin receptor for culling damaged mitochondria. Science 340:471–475

6 Chen H, Chomyn A, Chan DC (2005) Disruption of fusion results in mitochondrial heterogeneity and dysfunction. J Biol Chem 280:26185–26192

7 Chen L, Wang K, Long A, Jia L, Zhang Y, Deng H, Li Y, Han J, Wang Y (2017) Fasting-induced hormonal regulation of lysosomal function. Cell Res 27:748–763

8 Christofk HR, Vander Heiden MG, Harris MH, Ramanathan A, Gerszten RE, Wei R, Fleming MD, Schreiber SL, Cantley LC (2008a) The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature 452:230–233

9 Christofk HR, Vander Heiden MG, Wu N, Asara JM, Cantley LC (2008b) Pyruvate kinase M2 is a phosphotyrosine-binding protein. Nature 452:181–186

10 Cornu M, Albert V, Hall MN (2013) mTOR in aging, metabolism, and cancer. Curr Opin Genet Dev 23:53–62

11 Dayton TL, Jacks T, Vander Heiden MG (2016) PKM2, cancer metabolism, and the road ahead. EMBO Rep 17:1721–1730

12 Fantin VR, St-Pierre J, Leder P (2006) Attenuation of LDH-A expression uncovers a link between glycolysis, mitochondrial physiology, and tumor maintenance. Cancer Cell 9:425–434

13 Garcia D, Shaw RJ (2017) AMPK: mechanisms of cellular energy sensing and restoration of metabolic balance. Mol Cell 66:789–800

14 Gogvadze V, Orrenius S, Zhivotovsky B (2008) Mitochondria in cancer cells: what is so special about them? Trends Cell Biol 18:165–173

15 Gong G, Song M, Csordas G, Kelly DP, Matkovich SJ, Dorn GW 2nd (2015) Parkin-mediated mitophagy directs perinatal cardiac metabolic maturation in mice. Science 350:aad2459

16 Han J,Li E, Chen L, Zhang Y, Wei F, Liu J, Deng H, Wang Y (2015) The CREB coactivator CRTC2 controls hepatic lipid metabolism by regulating SREBP1. Nature 524:243–246

17 Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674

18 Hsu PP, Kang SA, Rameseder J, Zhang Y, Ottina KA, Lim D, Peterson TR, Choi Y,Gray NS, Yaffe MB (2011) The mTORregulated phosphoproteome reveals a mechanism of mTORC1-mediated inhibition of growth factor signaling. Science 332:1317–1322

19 Israelsen WJ, Dayton TL, Davidson SM, Fiske BP, Hosios AM, Bellinger G, Li J, Yu Y, Sasaki M, Horner JW (2013) PKM2 isoform-specific deletion reveals a differential requirement for pyruvate kinase in tumor cells. Cell 155:397–409

20 Keller KE, Tan IS, Lee YS (2012) SAICAR stimulates pyruvate kinase isoform M2 and promotes cancer cell survival in glucoselimited conditions. Science 338:1069–1072

21 Lazarou M, Sliter DA, Kane LA, Sarraf SA, Wang C, Burman JL, Sideris DP, Fogel AI, Youle RJ (2015) The ubiquitin kinase PINK1 recruits autophagy receptors to induce mitophagy. Nature 524:309–314

22 Liesa M, Shirihai OS (2013) Mitochondrial dynamics in the regulation of nutrient utilization and energy expenditure. Cell Metab 17:491–506

23 Mishra P, Chan DC (2014) Mitochondrial dynamics and inheritance during cell division, development and disease. Nat Rev Mol Cell Biol 15:634–646

24 Mourier A, Motori E, Brandt T, Lagouge M, Atanassov I, Galinier A, Rappl G, Brodesser S, Hultenby K, Dieterich C(2015) Mitofusin 2 is required to maintain mitochondrial coenzyme Q levels. J Cell Biol 208:429–442

25 Rehman J, Zhang HJ, Toth PT, Zhang Y, Marsboom G, Hong Z, Salgia R, Husain AN, Wietholt C, Archer SL (2012) Inhibition of mitochondrial fission prevents cell cycle progression in lung cancer. FASEB J 26:2175–2186

26 Saxton RA, Sabatini DM (2017) mTOR signaling in growth, metabolism, and disease. Cell 168:960–976

27 Serasinghe MN, Wieder SY, Renault TT, Elkholi R, Asciolla JJ, Yao JL, Jabado O, Hoehn K, Kageyama Y, Sesaki H (2015) Mitochondrial division is requisite to RAS-induced transformation and targeted by oncogenic MAPK pathway inhibitors. Mol Cell 57:521–536

28 Song Z, Ghochani M, McCaffery JM, Frey TG, Chan DC (2009) Mitofusins and OPA1 mediate sequential steps in mitochondrial membrane fusion. Mol Biol Cell 20:3525–3532

29 Valentini G, Chiarelli LR, Fortin R, Dolzan M, Galizzi A, Abraham DJ, Wang C, Bianchi P, Zanella A, Mattevi A (2002) Structure and function of human erythrocyte pyruvate kinase. Molecular basis of nonspherocytic hemolytic anemia. J Biol Chem 277:23807–23814

30 Vander Heiden MG, DeBerardinis RJ (2017) Understanding the intersections between metabolism and cancer biology. Cell 168:657–669

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

32 Wang C, Chiarelli LR, Bianchi P, Abraham DJ, Galizzi A, Mattevi A, Zanella A, Valentini G (2001) Human erythrocyte pyruvate kinase: characterization of the recombinant enzyme and a mutant form (R510Q) causing nonspherocytic hemolytic anemia. Blood 98:3113–3120

33 Yang W, Lu Z (2015) Pyruvate kinase M2 at a glance. J Cell Sci 128:1655–1660

34 Youle RJ, van der Bliek AM (2012) Mitochondrial fission, fusion, and stress. Science 337:1062–1065

35 Zhang CS, Hawley SA, Zong Y, Li M, Wang Z, Gray A, Ma T, Cui J, Feng JW, Zhu M (2017) Fructose-1,6-bisphosphate and aldolase mediate glucose sensing by AMPK. Nature 548:112–116

36 Zhao J, Zhang J, Yu M, Xie Y, Huang Y, Wolff DW, Abel PW, Tu Y (2013) Mitochondrial dynamics regulates migration and invasion of breast cancer cells. Oncogene 32:4814–4824