Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

Mitochondrial hexokinases, novel mediators of the antiapoptotic effects of growth factors and Akt

Oncogene volume 25, pages 4683–4696 (2006)Cite this article

Abstract

Cell survival has been closely linked to both trophic growth factor signaling and cellular metabolism. Such couplings have obvious physiologic and pathophysiologic implications, but their underlying molecular bases remain incompletely defined. As a common mediator of both the metabolic and anti-apoptotic effects of growth factors, the serine/threonine kinase Akt – also known as protein kinase B or PKB – is capable of regulating and coordinating these inter-related processes. The glucose dependence of the antiapoptotic effects of growth factors and Akt plus a strong correlation between Akt-regulated mitochondrial hexokinase association and apoptotic susceptibility suggest a major role for hexokinases in these effects. Mitochondrial hexokinases catalyse the first obligatory step of glucose metabolism and directly couple extramitochondrial glycolysis to intramitochondrial oxidative phosphorylation, and are thus well suited to play this role. The ability of Akt to regulate energy metabolism appears to have evolutionarily preceded the capacity to control cell survival. This suggests that Akt-dependent metabolic regulatory functions may have given rise to glucose-dependent antiapoptotic effects that evolved as an adaptive sensing system involving hexokinases and serve to ensure mitochondrial homeostasis, thereby coupling metabolism to cell survival. We hypothesize that the enlistment of Akt and hexokinase in the control of mammalian cell apoptosis evolved as a response to the recruitment of mitochondria to the apoptotic cascade. The central importance of mitochondrial hexokinases in cell survival also suggests that they may represent viable therapeutic targets in cancer.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  • Aleshin AE, Zeng C, Bourenkov GP, Bartunik HD, Fromm HJ, Honzatko RB . (1998). Structure 6: 39–50.

  • Allen CB, Guo X-L, White CW . (1998). Am J Physiol Lung Cell Mol Physiol 274: L320–L329.

  • Anderson JW, Herman RH, Tyrrell JB, Cohn RM . (1971). Am J Clin Nutr 24: 642–650.

  • Ardail D, Privat J-P, Egret-Charlier M, Levrat C, Lerme F, Louisot P . (1990). J Biol Chem 265: 18797–18802.

  • Ardehali H, Printz RL, Whitesell RR, May JM, Granner DK . (1999). J Biol Chem 274: 15986–15989.

  • Ardehali H, Yano Y, Printz RL, Koch S, Whitesell RR, May JM et al. (1996). J Biol Chem 271: 1849–1852.

  • Arora KK, Filburn CR, Pedersen PL . (1993). J Biol Chem 268: 18259–18266.

  • Arora KK, Pedersen PL . (1988). J Biol Chem 263: 17422–17428.

  • Azoulay-Zohar H, Aflalo C . (1999). J Bioenerg Biomembr 31: 569–579.

  • Azoulay-Zohar H, Aflalo C . (2000). Eur J Biochem 267: 2973–2980.

  • Azoulay-Zohar H, Israelson A, Abu-Hamad S, Shoshan-Barmatz V . (2004). Biochem J 377: 347–355.

  • BeltrandelRio H, Wilson JE . (1991). Arch Biochem Biophys 286: 183–194.

  • BeltrandelRio H, Wilson JE . (1992a). Arch Biochem Biophys 299: 667–677.

  • BeltrandelRio H, Wilson JE . (1992b). Arch Biochem Biophys 299: 116–124.

  • Beutner G, Rück A, Riede B, Brdiczka D . (1998). Biochim Biophys Acta 1368: 7–18.

  • Beutner G, Rück A, Riede B, Welte W, Brdiczka D . (1996). FEBS Lett 396: 189–195.

  • Breckenridge DG, Xue D . (2004). Curr Opin Cell Biol 16: 647–652.

  • Bryson JM, Coy PE, Gottlob K, Hay N, Robey RB . (2002). J Biol Chem 277: 11392–11400.

  • Bustamante E, Morris HP, Pedersen PL . (1981). J Biol Chem 256: 8699–8704.

  • Bustamante E, Pedersen PL . (1977). Proc Natl Acad Sci USA 74: 3735–3739.

  • Bustamante E, Pediaditakis P, He L, Lemasters JJ . (2005). Biochem Biophys Res Commun 334: 907–910.

  • Cardenas ML, Cornish-Bowden A, Ureta T . (1998). Biochim Biophys Acta 1401: 242–264.

  • Colombini M . (2004). Mol Cell Biochem 256/257: 107–115.

  • Colowick SP . (1973). In: Boyer PD (ed). The Enzymes, Vol. 9. Academic Press: New York, pp 1–48.

    Google Scholar 

  • Coy PE, Taneja N, Lee I, Hecquet C, Bryson JM, Robey RB . (2002). Am J Physiol Renal Physiol 283: F271–F279.

  • Crane RK, Sols A . (1953). J Biol Chem 203: 273–292.

  • Dang CV, Semenza GL . (1999). Trends Biochem Sci 24: 68–73.

  • Danial NN, Gramm CF, Scorrano L, Zhang C-Y, Krauss S, Ranger AM et al. (2003). Nature 424: 952–956.

  • Danial NN, Korsmeyer SJ . (2004). Cell 116: 205–219.

  • de Cerqueira Cesar M, Wilson JE . (1995). Arch Biochem Biophys 324: 9–14.

  • de Cerqueira Cesar M, Wilson JE . (1998). Arch Biochem Biophys 350: 109–117.

  • De Pinto V, Al Jamal JA, Palmieri F . (1993). J Biol Chem 268: 12977–12982.

  • De Pinto V, Tommasino M, Benz R, Palmieri F . (1985). Biochim Biophys Acta 813: 230–242.

  • Desagher S, Martinou J-C . (2000). Trends Cell Biol 10: 369–377.

  • Easterby JS, O'Brien MJ . (1973). Eur J Biochem 38: 201–211.

  • Eggleston LV, Krebs HA . (1974). Biochem J 138: 425–435.

  • Epand RF, Martinou JC, Fornallaz-Mulhauser M, Hughes DW, Epand RM . (2002). J Biol Chem 277: 32632–32639.

  • Felgner PL, Messer JL, Wilson JE . (1979). J Biol Chem 254: 4946–4949.

  • Fico A, Paglialunga F, Cigliano L, Abrescia P, Verde P, Martini G et al. (2004). Cell Death Differentiation 11: 823–831.

  • Fiek C, Benz R, Roos N, Brdiczka D . (1982). Biochim Biophys Acta 688: 429–440.

  • Gao Z, Shao Y, Jiang X . (2005). J Biol Chem 280: 38271–38275.

  • Garrido C, Kroemer G . (2004). Curr Opin Cell Biol 16: 639–646.

  • Gelb BD, Adams V, Jones SN, Griffin LD, MacGregor GR, McCabe ERB . (1992). Proc Natl Acad Sci USA 89: 202–206.

  • Gottlieb E, Armour SM, Harris MH, Thompson CB . (2003). Cell Death Differentiation 10: 709–717.

  • Gottlieb E, Armour SM, Thompson CB . (2002). Proc Natl Acad Sci USA 99: 12801–12806.

  • Gottlob K, Majewski N, Kennedy S, Kandel E, Robey RB, Hay N . (2001). Genes Dev 15: 1406–1418.

  • Granner D, Pilkis S . (1990). J Biol Chem 265: 10173–10176.

  • Gumaa KA, McLean P . (1969). Biochem Biophys Res Commun 36: 771–779.

  • Guo Y, Srinivasula SM, Druilhe A, Fernandes-Alnemri T, Alnemri ES . (2002). J Biol Chem 277: 13430–13437.

  • Hahn-Windgassen A, Nogueira V, Chen CC, Skeen JE, Sonenberg N, Hay N . (2005). J Biol Chem 280: 32081–32089.

  • Hashimoto M, Wilson JE . (2000). Arch Biochem Biophys 384: 163–173.

  • Hay N . (2005). Cancer Cell 8: 179–183.

  • Hay N, Sonenberg N . (2004). Genes Dev 18: 1926–1945.

  • Horvitz HR . (2003). Chem Biol Chem 4: 697–711.

  • Inoki K, Zhu T, Guan K-L . (2003). Cell 115: 577–590.

  • Iynedjian PB . (1993). Biochem J 293: 1–13.

  • Jiang X, Wang X . (2004). Annu Rev Biochem 73: 87–106.

  • Kandel ES, Hay N . (1999). Exp Cell Res 253: 210–229.

  • Katzen HM, Schimke RT . (1965). Proc Natl Acad Sci USA 54: 1218–1225.

  • Katzen HM, Soderman DD . (1988). Arch Biochem Biophys 262: 626–635.

  • Katzen HM, Soderman DD, Wiley CE . (1970). J Biol Chem 245: 4081–4096.

  • Kennedy SG, Kandel ES, Cross TK, Hay N . (1999). Mol Cell Biol 19: 5800–5810.

  • Kurata M, Suzuki M, Agar NS . (2000). Comp Haematol Int 10: 59–67.

  • Kuwana T, Mackey MR, Perkins G, Ellisman MH, Latterich M, Schneiter R et al. (2002). Cell 111: 331–342.

  • Lassus P, Opitz-Araya X, Lazebnik Y . (2002). Science 297: 1352–1354.

  • Laterveer F, Nicolay K, BeltrandelRio H, Wilson JE . (1993). Arch Biochem Biophys 306: 285–286.

  • Le Goffe C, Vallette G, Charrier L, Candelon T, Bou-Hanna C, Bouhours J-F et al. (2002). Biochem J 364: 349–359.

  • Le Goffe C, Vallette G, Jarry A, Bou-Hanna C, Laboisse CL . (1999). Biochem J 344: 643–648.

  • Lindén M, Gellerfors P, Nelson BD . (1982). FEBS Lett 141: 189–192.

  • Lucken-Ardjomande S, Martinou J-C . (2005a). J Cell Sci 118: 473–483.

  • Lucken-Ardjomande S, Martinou JC . (2005b). CR Biol 328: 616–631.

  • Lutter M, Fang M, Luo X, Nishijima M, Xie X-S, Wang X . (2000). Nat Cell Biol 2: 754–756.

  • Lutter M, Perkins GA, Wang X . (2001). BMC Cell Biol 2: 22.

  • Majewski N, Nogueira V, Bhaskar P, Coy PE, Skeen JE, Gottlob K et al. (2004a). Mol Cell 16: 819–830.

  • Majewski N, Nogueira V, Robey RB, Hay N . (2004b). Mol Cell Biol 24: 730–740.

  • Majumder PK, Febbo PG, Bikoff R, Berger R, Xue Q, McMahon LM et al. (2004). Nat Med 10: 594–601.

  • Malaisse-Lagae F, Malaisse WJ . (1988). Biochem Med Metab Biol 39: 80–89.

  • Mathupala SP, Rempel A, Pedersen PL . (1997). J Bioenerg Biomemb 29: 339–343.

  • Miccoli L, Beurdeley-Thomas A, De Pinieux G, Sureau F, Oudard S, Dutrillaux B et al. (1998). Cancer Res 58: 5777–5786.

  • Miccoli L, Oudard S, Sureau F, Poirson F, Dutrillaux B, Poupon M-F . (1996). Biochem J 313: 957–962.

  • Moley KH, Mueckler MM . (2000). Apoptosis 5: 99–105.

  • Nakashima RA, Mangan PS, Colombini M, Pedersen PL . (1986). Biochemistry 25: 1015–1021.

  • Newmeyer DD, Ferguson-Miller S . (2003). Cell 112: 481–490.

  • Nutt LK, Margolis SS, Jensen M, Herman CE, Dunphy WG, Rathmell JC et al. (2005). Cell 123: 89–103.

  • Osawa H, Printz RL, Whitesell RR, Granner DK . (1995). Diabetes 44: 1426–1432.

  • Östlund AK, Gohring U, Krause J, Brdiczka D . (1983). Biochem Med 30: 231–245.

  • Oudard S, Poirson F, Miccoli L, Bourgeois Y, Vassault A, Poisson M et al. (1995). Int J Cancer 62: 216–222.

  • Parry DM, Pedersen PL . (1983). J Biol Chem 258: 10904–10912.

  • Parry DM, Pedersen PL . (1984). J Biol Chem 259: 8917–8923.

  • Pastorino JG, Hoek JB, Shulga N . (2005). Cancer Res 65: 10545–10554.

  • Pastorino JG, Shulga N, Hoek JB . (2002). J Biol Chem 277: 7610–7618.

  • Pedersen PL, Mathupala S, Rempel A, Geschwind JF, Ko YH . (2002). Biochim Biophys Acta 1555: 14–20.

  • Penso J, Beitner R . (1998). Eur J Pharmacol 342: 113–117.

  • Penso J, Beitner R . (2003). Mol Genet Metab 78: 74–78.

  • Plas DR, Talapatra S, Edinger AL, Rathmell JC, Thompson CB . (2001). J Biol Chem 276: 12041–12048.

  • Polakis PG, Wilson JE . (1985). Arch Biochem Biophys 236: 328–337.

  • Postic C, Shiota M, Magnuson MA . (2001). Recent Prog Horm Res 56: 195–217.

  • Preller A, Wilson JE . (1992). Arch Biochem Biophys 294: 482–492.

  • Rathmell JC, Fox CJ, Plas DR, Hammerman PS, Cinalli RM, Thompson CB . (2003). Mol Cell Biol 23: 7315–7328.

  • Riddle SR, Ahmad A, Ahmad S, Deeb SS, Makki M, Schneider BK et al. (2000). Am J Physiol Lung Cell Mol Physiol 278: L407–L416.

  • Robertson JD, Enoksson M, Suomela M, Zhivotovsky B, Orrenius S . (2002). J Biol Chem 277: 29803–29809.

  • Robey RB . (2003). J Leukoc Biol 74: 307–308.

  • Robey RB, Hay N . (2005a). Drug Discov Today Dis Mech 2: 239–246 (Erratum 2:389, 2005).

  • Robey RB, Hay N . (2005b). Cell Cycle 4: 654–658.

  • Robey RB, Ma J, Santos AVP, Noboa OA, Coy PE, Bryson JM . (2002). J Biol Chem 277: 14370–14378.

  • Rose IA, Warms JVB . (1967). J Biol Chem 242: 1635–1645.

  • Scorrano L, Oakes SA, Opferman JT, Cheng EH, Sorcinelli MD, Pozzan T et al. (2003). Science 300: 135–139.

  • Sebastian S, Hoebee B, Hande MP, Kenkare UW, Natarajan AT . (1997). Cytogenet Cell Genet 77: 266–267.

  • Seixas da-Silva W, Gomez-Puyou A, de Gomez-Puyou MT, Moreno-Sanchez R, De Felice FG, de Meis L et al. (2004). J Biol Chem 279: 39846–39855.

  • Shinohara Y, Hino M, Ishida T, Yamanaka Y, Terada H . (2001). Biochim Biophys Acta 1499: 242–248.

  • Shinohara Y, Sagawa I, Ichihara J, Yamamoto K, Terao K, Terada H . (1997). Biochim Biophys Acta 1319: 319–330.

  • Shinohara Y, Yamamoto K, Kogure K, Ichihara J, Terada H . (1994). Cancer Lett 82: 27–32.

  • Skaff DA, Kim CS, Tsai HJ, Honzatko RB, Fromm HJ . (2005). J Biol Chem 280: 38403–38409.

  • Smith TAD . (2001). Nuclear Med Biol 28: 1–4.

  • Sochor M, Baquer NZ, McLean P . (1979). Arch Biochem Biophys 198: 632–646.

  • Taneja N, Coy PE, Lee I, Bryson JM, Robey RB . (2004). Am J Physiol Cell Physiol 287: C548–C557.

  • Tian W-N, Braunstein LD, Apse K, Pang J, Rose M, Tian X et al. (1999). Am J Physiol Cell Physiol 276: C1121–C1131.

  • Tinel A, Tschopp J . (2004). Science 304: 843–846.

  • Tsai HJ . (1999). Arch Biochem Biophys 369: 149–156.

  • Tsai HJ, Wilson JE . (1996). Arch Biochem Biophys 329: 17–23.

  • Tsai HJ, Wilson JE . (1997). Arch Biochem Biophys 338: 183–192.

  • Tu S, McStay GP, Boucher LM, Mak T, Beere HM, Green DR . (2006). Nat Cell Biol 8: 72–77.

  • Ureta T, Radojkovic J, Bustamante E . (1983). Biochem Int 7: 585–592.

  • Vander Heiden MG, Chandel NS, Li XX, Schumacker PT, Colombini M, Thompson CB . (2000). Proc Natl Acad Sci USA 97: 4666–4671.

  • Vander Heiden MG, Chandel NS, Schumacker PT, Thompson CB . (1999). Mol Cell 3: 159–167.

  • Vignot S, Faivre S, Aguirre D, Raymond E . (2005). Ann Oncol 16: 525–537.

  • Vyssokikh MY, Brdiczka D . (2003). Acta Biochim Polonica 50: 398–404.

  • Vyssokikh MY, Goncharova NY, Zhuravlyova AV, Zorova LD, Kirichenko VV, Krasnikov BF et al. (1999). Biochemistry (Moscow) 64: 390–398.

  • Vyssokikh MY, Katz A, Rueck A, Wuensch C, Dörner A, Zorov DB et al. (2001). Biochem J 358: 349–358.

  • Wagner KW, Engels IH, Deveraux QL . (2004). J Biol Chem 279: 35047–35052.

  • Warburg O . (1956). Science 123: 309–314.

  • White TK, Wilson JE . (1987). Arch Biochem Biophys 259: 402–411.

  • White TK, Wilson JE . (1989). Arch Biochem Biophys 274: 375–393.

  • Whitesell RR, Ardehali H, Beechem JM, Powers AC, Van der Meer W, Perriott LM et al. (2005). Biochem J 386: 245–253.

  • Wilson JE . (1973). Arch Biochem Biophys 159: 543–549.

  • Wilson JE . (1978). Trends Biochem Sci, 124–125.

  • Wilson JE . (1985). In: Beitner R (ed). Regulation of Carbohydrate Metabolism, Vol. I CRC Press: Boca Raton, pp 45–85.

    Google Scholar 

  • Wilson JE . (1995). Rev Physiol Biochem Pharmacol 126: 65–198.

  • Wilson JE . (1997a). Biochem Soc Trans 25: 103–107.

  • Wilson JE . (1997b). J Bioenerg Biomembr 29: 97–102.

  • Wilson JE . (2003). J Exp Biol 206: 2049–2057.

  • Wilson JE, Felgner PL . (1977). Mol Cell Biochem 18: 39–47.

  • Xie G, Wilson JE . (1990). Arch Biochem Biophys 276: 285–293.

  • Xu LZ, Harrison RW, Weber IT, Pilkis SJ . (1995). J Biol Chem 270: 9939–9946.

  • Zaid H, Abu-Hamad S, Israelson A, Nathan I, Shoshan-Barmatz V . (2005). Cell Death Differentiation 12: 751–760.

  • Zhivotovsky B, Orrenius S . (2005). Biochem Biophys Res Commun 331: 859–867.

Download references

Acknowledgements

Owing to space constraints, selected reviews have been frequently cited in lieu of primary sources. We apologize to those investigators whose original reports are not directly referenced herein. The authors' laboratories are supported by National Institutes of Health grants CA090764 (NH) and AG016927 (NH), a Veterans Administration Merit Review Award (RBR), and American Heart Association Established Investigator Award 0440141N (RBR).

Author information

Authors and Affiliations

  1. Research and Development Service, White River Junction VA Medical Center, White River Junction, VT, USA

    R B Robey

  2. Departments of Medicine and Physiology, Dartmouth Medical School, NH, Lebanon, USA

    R B Robey

  3. Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, IL, Chicago, USA

    N Hay

Authors
  1. R B Robey
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. N Hay
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to R B Robey or N Hay.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Robey, R., Hay, N. Mitochondrial hexokinases, novel mediators of the antiapoptotic effects of growth factors and Akt. Oncogene 25, 4683–4696 (2006). https://doi.org/10.1038/sj.onc.1209595

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1209595

Keywords

This article is cited by

Search

Advanced search

Quick links