Volume 10 Issue 8
Aug.  2019
Turn off MathJax
Article Contents
Tong Li, Jinbo Han, Liangjie Jia, Xiao Hu, Liqun Chen, Yiguo Wang. PKM2 coordinates glycolysis with mitochondrial fusion and oxidative phosphorylation[J]. Protein&Cell, 2019, 10(8): 583-594. doi: 10.1007/s13238-019-0618-z
Citation: Tong Li, Jinbo Han, Liangjie Jia, Xiao Hu, Liqun Chen, Yiguo Wang. PKM2 coordinates glycolysis with mitochondrial fusion and oxidative phosphorylation[J]. Protein&Cell, 2019, 10(8): 583-594. doi: 10.1007/s13238-019-0618-z

PKM2 coordinates glycolysis with mitochondrial fusion and oxidative phosphorylation

doi: 10.1007/s13238-019-0618-z

We thank Drs. Peng Jiang, Li Yu and Suneng Fu for helpful discussion. This work was supported by grants from the Ministry of Science and Technology of the People's Republic of China (2017YFA0503404 and 2016YFC1304803), and the National Natural Science Foundation of China (Grant Nos. 31625014, 31621063 and 31830040).

  • Received Date: 2019-02-13
  • Rev Recd Date: 2019-02-26
  • 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.
  • loading
  • [1]
    Anastasiou D, Yu Y, Israelsen WJ, Jiang JK, Boxer MB, Hong BS, Tempel W, Dimov S, Shen M, Jha A et al (2012) Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis. Nat Chem Biol 8:839-847
    Buck MD, O'Sullivan D, Klein Geltink RI, Curtis JD, Chang CH, Sanin DE, Qiu J, Kretz O, Braas D, van der Windt GJ et al (2016)Mitochondrial dynamics controls T cell fate through metabolic programming. Cell 166:63-76
    Chaneton B, Hillmann P, Zheng L, Martin ACL, Maddocks ODK, Chokkathukalam A, Coyle JE, Jankevics A, Holding FP, Vousden KH et al (2012) Serine is a natural ligand and allosteric activator of pyruvate kinase M2. Nature 491:458-462
    Chen H, Chan DC (2017) Mitochondrial dynamics in regulating the unique phenotypes of cancer and stem cells. Cell Metab 26:39- 48
    Chen Y, Dorn GW 2nd (2013) PINK1-phosphorylated mitofusin 2 is a Parkin receptor for culling damaged mitochondria. Science 340:471-475
    Chen H, Chomyn A, Chan DC (2005) Disruption of fusion results in mitochondrial heterogeneity and dysfunction. J Biol Chem 280:26185-26192
    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
    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
    Christofk HR, Vander Heiden MG, Wu N, Asara JM, Cantley LC (2008b) Pyruvate kinase M2 is a phosphotyrosine-binding protein. Nature 452:181-186
    Cornu M, Albert V, Hall MN (2013) mTOR in aging, metabolism, and cancer. Curr Opin Genet Dev 23:53-62
    Dayton TL, Jacks T, Vander Heiden MG (2016) PKM2, cancer metabolism, and the road ahead. EMBO Rep 17:1721-1730
    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
    Garcia D, Shaw RJ (2017) AMPK:mechanisms of cellular energy sensing and restoration of metabolic balance. Mol Cell 66:789- 800
    Gogvadze V, Orrenius S, Zhivotovsky B (2008) Mitochondria in cancer cells:what is so special about them? Trends Cell Biol 18:165-173
    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
    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
    Hanahan D, Weinberg RA (2011) Hallmarks of cancer:the next generation. Cell 144:646-674
    Hsu PP, Kang SA, Rameseder J, Zhang Y, Ottina KA, Lim D, Peterson TR, Choi Y, Gray NS, Yaffe MB et al (2011) The mTORregulated phosphoproteome reveals a mechanism of mTORC1-mediated inhibition of growth factor signaling. Science 332:1317- 1322
    Israelsen WJ, Dayton TL, Davidson SM, Fiske BP, Hosios AM, Bellinger G, Li J, Yu Y, Sasaki M, Horner JW et al (2013) PKM2 isoform-specific deletion reveals a differential requirement for pyruvate kinase in tumor cells. Cell 155:397-409
    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
    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
    Liesa M, Shirihai OS (2013) Mitochondrial dynamics in the regulation of nutrient utilization and energy expenditure. Cell Metab 17:491- 506
    Mishra P, Chan DC (2014) Mitochondrial dynamics and inheritance during cell division, development and disease. Nat Rev Mol Cell Biol 15:634-646
    Mourier A, Motori E, Brandt T, Lagouge M, Atanassov I, Galinier A, Rappl G, Brodesser S, Hultenby K, Dieterich C et al (2015)
    Mitofusin 2 is required to maintain mitochondrial coenzyme Q levels. J Cell Biol 208:429-442
    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
    Saxton RA, Sabatini DM (2017) mTOR signaling in growth, metabolism, and disease. Cell 168:960-976
    Serasinghe MN, Wieder SY, Renault TT, Elkholi R, Asciolla JJ, Yao JL, Jabado O, Hoehn K, Kageyama Y, Sesaki H et al (2015)Mitochondrial division is requisite to RAS-induced transformation and targeted by oncogenic MAPK pathway inhibitors. Mol Cell 57:521-536
    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
    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
    Vander Heiden MG, DeBerardinis RJ (2017) Understanding the intersections between metabolism and cancer biology. Cell 168:657-669
    Vander Heiden MG, Cantley LC, Thompson CB (2009) Understanding the Warburg effect:the metabolic requirements of cell proliferation. Science 324:1029-1033
    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
    Yang W, Lu Z (2015) Pyruvate kinase M2 at a glance. J Cell Sci 128:1655-1660
    Youle RJ, van der Bliek AM (2012) Mitochondrial fission, fusion, and stress. Science 337:1062-1065
    Zhang CS, Hawley SA, Zong Y, Li M, Wang Z, Gray A, Ma T, Cui J, Feng JW, Zhu M et al (2017) Fructose-1,6-bisphosphate and aldolase mediate glucose sensing by AMPK. Nature 548:112- 116
    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
  • 加载中


    通讯作者: 陈斌, bchen63@163.com
    • 1. 

      沈阳化工大学材料科学与工程学院 沈阳 110142

    1. 本站搜索
    2. 百度学术搜索
    3. 万方数据库搜索
    4. CNKI搜索


    Article Metrics

    Article views (1226) PDF downloads(177) Cited by()
    Proportional views


    DownLoad:  Full-Size Img  PowerPoint