Skip to main content
SpringerLink
Log in

Hexokinase-mitochondrial interaction in cardiac tissue: implications for cardiac glucose uptake, the 18FDG lumped constant and cardiac protection

  • Published:
Journal of Bioenergetics and Biomembranes Aims and scope Submit manuscript

Abstract

The hexokinases are fundamental regulators of cardiac glucose uptake; by phosphorylating free intracellular glucose, they maintain the concentration gradient driving myocardial extraction of glucose from the bloodstream. Hexokinases are highly regulated proteins, subject to activation by insulin, hypoxia or ischaemia, and inhibition by their enzymatic product glucose-6-phosphate. In vitro and in many non-cardiac cell types, hexokinases have been shown to bind to the mitochondria, both increasing their phosphorylative capacity, and having a putative role in the anti-apoptotic function of protein kinase B (PKB)/Akt. Whether hexokinase-mitochondrial interaction is a dynamic and responsive process in the heart has been difficult to prove, but there is growing evidence that this association does indeed increase in response to insulin stimulation or ischaemia. In this review I discuss the relevance of hexokinase-mitochondrial interaction to cardiac glycolytic control, our interpretation of 18FDG cardiac PET scans, and its possible role in protecting the myocardium from ischaemic injury.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Abraham S, Borrebaek B, Chaikoff IL (1964) Effect of Dietary Carbohydrate on Glucokinase and Mannokinase Activities of Various Rat Tissues. J. Nutr. 83:273–288

    CAS  Google Scholar 

  • Anflous-Pharayra K, Cai ZJ, Craigen WJ (2007) VDAC1 serves as a mitochondrial binding site for hexokinase in oxidative muscles. Biochim Biophys Acta 1767:136–42

    Article  CAS  Google Scholar 

  • Ardehali H, Printz RL, Whitesell RR, May JM, Granner DK (1999) Functional Interaction between the N- and C-terminal Halves of Human Hexokinase II. J. Biol. Chem. 274:15986–15989

    Article  CAS  Google Scholar 

  • Ardehali H, Yano Y, Printz RL, Koch S, Whitesell RR, May JM, Granner DK (1996) Functional Organization of Mammalian Hexokinase II. J. Biol. Chem. 271:1849–1852

    Article  CAS  Google Scholar 

  • Arora KK, Filburn CR, Pedersen PL (1993) Structure/function relationships in hexokinase. Site-directed mutational analyses and characterization of overexpressed fragments implicate different functions for the N- and C-terminal halves of the enzyme. J. Biol. Chem. 268:18259–18266

    CAS  Google Scholar 

  • Arora KK, Pedersen PL (1988) Functional significance of mitochondrial bound hexokinase in tumor cell metabolism. Evidence for preferential phosphorylation of glucose by intramitochondrially generated ATP. J Biol Chem 263:17422–17428

    CAS  Google Scholar 

  • Belke DD, Larsen TS, Gibbs EM, Severson DL (2001) Glucose metabolism in perfused mouse hearts overexpressing human GLUT-4 glucose transporter. Am J Physiol Endocrinol Metab 280:E420–427

    CAS  Google Scholar 

  • BeltrandelRio H, Wilson JE (1992) Interaction of mitochondrially bound rat brain hexokinase with intramitochondrial compartments of ATP generated by oxidative phosphorylation and creatine kinase. Archives of Biochemistry and Biophysics 299:116–124

    Article  CAS  Google Scholar 

  • Beutner G, Ruck A, Riede B, Brdiczka D (1998) Complexes between porin, hexokinase, mitochondrial creatine kinase and adenylate translocator display properties of the permeability transition pore. Implication for regulation of permeability transition by the kinases. Biochimica et Biophysica Acta (BBA)/Biomembranes 1368:7–18

    Article  CAS  Google Scholar 

  • Birnbaum MJ (2004) On the InterAktion between Hexokinase and the Mitochondrion. 7:781–782

    CAS  Google Scholar 

  • Borrebaek B, Haviken JT (1985) Some observations on mitochondrial-bound hexokinase and creatine kinase of the heart. Biochem Med 33:170–9

    Article  CAS  Google Scholar 

  • Crane PD, William MP, Leon DB, Oldendorf WH (1983) Kinetics of Transport and Phosphorylation of 2-Fluoro-2-Deoxy-d-Glucose in Rat Brain. In Journal of Neurochemistry, pp. 160–167

  • Cross DAE, Alessi DR, Cohen P, Andjelkovich M, Hemmings BA (1995) Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature 378:785–789

    Article  CAS  Google Scholar 

  • da Silva WS, Da Silva WS, Gomez-Puyou A, De Gomez-Puyou MT, Moreno-Sanchez R, de Felice FG, de Meis L, Oliveira MF, Galina A (2004) Mitochondrial Bound Hexokinase Activity as a Preventive Antioxidant Defense: steady-state ADP formation as a regulatory mechanism of mambrane potential and reactive oxygen species generation in mitochondria. J Biol Chem 279:39846–39855

    Article  Google Scholar 

  • Davey KA, Garlick PB, Warley A, Southworth R (2007) Immunogold labeling study of the distribution of GLUT-1 and GLUT-4 in cardiac tissue following stimulation by insulin or ischemia. Am J Physiol Heart Circ Physiol 292:H2009–19

    Article  CAS  Google Scholar 

  • de Cerqueira Cesar M, Wilson JE (1998) Further Studies on the Coupling of Mitochondrially Bound Hexokinase to Intramitochondrially Compartmented ATP, Generated by Oxidative Phosphorylation. Archives of Biochemistry and Biophysics 350:109–117

    Article  Google Scholar 

  • Desagher S, Martinou J-C (2000) Mitochondria as the central control point of apoptosis. Trends in Cell Biology 10:369–377

    Article  CAS  Google Scholar 

  • Doenst T, Han Q, Goodwin GW, Guthrie PH, Taegtmeyer H (1998) Insulin does not change the intracellular distribution of hexokinase in rat heart. Am J Physiol 275:E558–67

    CAS  Google Scholar 

  • Doenst T, Taegtmeyer H (1998) Profound underestimation of glucose uptake by [18F]2-deoxy-2-fluoroglucose in reperfused rat heart muscle. Circulation 97:2454–62

    CAS  Google Scholar 

  • Fueger PT, Heikkinen S, Bracy DP, Malabanan CM, Pencek RR, Laakso M, Wasserman DH (2003) Hexokinase II partial knockout impairs exercise-stimulated glucose uptake in oxidative muscles of mice. Am J Physiol Endocrinol Metab 285:E958–63

    CAS  Google Scholar 

  • Fueger PT, Lee-Young RS, Shearer J, Bracy DP, Heikkinen S, Laakso M, Rottman JN, Wasserman DH (2007) Phosphorylation barriers to skeletal and cardiac muscle glucose uptakes in high-fat fed mice: studies in mice with a 50% reduction of hexokinase II. Diabetes 56:2476–84

    Article  CAS  Google Scholar 

  • Garlick PB, Medina RA, Southworth R, Marsden PK (1999) Differential uptake of FDG and DG during post-ischaemic reperfusion in the isolated, perfused rat heart. Eur J Nucl Med 26:1353–8

    Article  CAS  Google Scholar 

  • Gimenez-Cassina A, Lim F, Cerrato T, Palomo GM, Diaz-Nido J (2009) Mitochondrial Hexokinase II Promotes Neuronal Survival and Acts Downstream of Glycogen Synthase Kinase-3. J. Biol. Chem. 284:3001–3011

    Article  CAS  Google Scholar 

  • Goldin N, Arzoine L, Heyfets A, Israelson A, Zaslavsky Z, Bravman T, Bronner V, Notcovich A, Shoshan-Barmatz V, Flescher E (2008) Methyl jasmonate binds to and detaches mitochondria-bound hexokinase. Oncogene 27:4636–4643

    Article  CAS  Google Scholar 

  • Gottlob K, Majewski N, Kennedy S, Kandel E, Robey RB, Hay N (2001) Inhibition of early apoptotic events by Akt PKB is dependent on the first committed step of glycolysis and mitochondrial hexokinase. Genes & Development 15:1406–1418

    Article  CAS  Google Scholar 

  • Gray SM, Adams V, Yamashita Y, Le SP, Goddardfinegold J, McCabe ERB (1994) Hexokinase Binding in Ischemic and Reperfused Piglet Brain. Biochemical Medicine and Metabolic Biology 53:145–148

    Article  CAS  Google Scholar 

  • Halseth AE, Bracy DP, Wasserman DH (1999) Overexpression of hexokinase II increases insulinand exercise-stimulated muscle glucose uptake in vivo. Am J Physiol Endocrinol Metab 276:E70–77

    CAS  Google Scholar 

  • Herrero P, Kisrieva-Ware Z, Dence CS, Patterson B, Coggan AR, Han D-H, Ishii Y, Eisenbeis P, Gropler RJ (2007) PET Measurements of Myocardial Glucose Metabolism with 1-11C-Glucose and Kinetic Modeling. J Nucl Med 48:955–964

    Article  CAS  Google Scholar 

  • Heusch G, Schulz R, Rahimtoola SH (2005) Myocardial hibernation: a delicate balance. Am J Physiol Heart Circ Physiol 288:H984–999

    Article  CAS  Google Scholar 

  • Jonassen AK, Sack MN, Mjos OD, Yellon DM (2001) Myocardial Protection by Insulin at Reperfusion Requires Early Administration and Is Mediated via Akt and p70s6 Kinase Cell-Survival Signaling. Circulation Research 89:1191–1198

    Article  CAS  Google Scholar 

  • Juhaszova M, Wang S, Zorov DB, Nuss HB, Gleichmann M, Mattson MP, Sollott SJ (2008) The identity and regulation of the mitochondrial permeability transition pore: where the known meets the unknown. Ann N Y Acad Sci 1123:197–212

    Article  CAS  Google Scholar 

  • Knuuti MJ, Nuutila P, Ruotsalainen U, Teras M, Saraste M, Harkonen R, Ahonen A, Wegelius U, Haapanen A, Bergman J et al (1993) The Value of Quantitative Analysis of Glucose Utilization in Detection of Myocardial Viability by PET. J Nucl Med 34:2068–2075

    CAS  Google Scholar 

  • Kodde IF, van der Stok J, Smolenski RT, de Jong JW (2007) Metabolic and genetic regulation of cardiac energy substrate preference. Comparative Biochemistry and Physiology - Part A: Molecular & Integrative Physiology 146:26–39

    Article  Google Scholar 

  • Lewis JS, Herrero P, Sharp TL, Engelbach JA, Fujibayashi Y, Laforest R, Kovacs A, Gropler RJ, Welch MJ (2002) Delineation of Hypoxia in Canine Myocardium Using PET and Copper(II)-Diacetyl-bis(N4-Methylthiosemicarbazone). J Nucl Med 43:1557–1569

    Google Scholar 

  • Liedtke AJ, Renstrom B, Nellis SH (1992) Correlation between [5-3H]glucose and [U-14C]deoxyglucose as markers of glycolysis in reperfused myocardium. Circulation Research 71:689–700

    CAS  Google Scholar 

  • Lindén M, Gellerfors P, Dean Nelson B (1982) Pore protein and the hexokinase-binding protein from the outer membrane of rat liver mitochondria are identical. FEBS Letters 141:189–192

    Article  Google Scholar 

  • Liu X, Kim CS, Kurbanov FT, Honzatko RB, Fromm HJ (1999) Dual Mechanisms for Glucose 6-Phosphate Inhibition of Human Brain Hexokinase. J. Biol. Chem. 274:31155–31159

    Article  CAS  Google Scholar 

  • Lynch RM, Fogarty KE, Fay FS (1991) Modulation of hexokinase association with mitochondria analyzed with quantitative three-dimensional confocal microscopy. J. Cell Biol. 112:385–395

    Article  CAS  Google Scholar 

  • Majewski N, Nogueira V, Bhaskar P, Coy PE, Skeen JE, Gottlob K, Chandel NS, Thompson CB, Robey RB, Hay N (2004) Hexokinase-Mitochondria Interaction Mediated by Akt Is Required to Inhibit Apoptosis in the Presence or Absence of Bax and Bak. Molecular Cell 16:819–830

    Article  CAS  Google Scholar 

  • Manchester J, Kong X, Nerbonne J, Lowry OH, Lawrence JC Jr (1994) Glucose transport and phosphorylation in single cardiac myocytes: rate-limiting steps in glucose metabolism. Am J Physiol 266:E326–33

    CAS  Google Scholar 

  • Matsui T, Nagoshi T, Hong EG, Luptak I, Hartil K, Li L, Gorovits N, Charron MJ, Kim JK, Tian R et al. (2006) Effects of chronic Akt activation on glucose uptake in the heart. Am J Physiol Endocrinol Metab 290:E789–97

    Article  CAS  Google Scholar 

  • Matsui T, Rosenzweig A (2005) Convergent signal transduction pathways controlling cardiomyocyte survival and function: the role of PI 3-kinase and Akt. Journal of Molecular and Cellular Cardiology 38:63–71

    Article  CAS  Google Scholar 

  • Matsui T, Tao J, del Monte F, Lee K-H, Li L, Picard M, Force TL, Franke TF, Hajjar RJ, Rosenzweig A (2001) Akt Activation Preserves Cardiac Function and Prevents Injury After Transient Cardiac Ischemia In Vivo. Circulation 104:330–335

    CAS  Google Scholar 

  • Miyamoto S, Murphy AN, Brown JH (2008) Akt mediates mitochondrial protection in cardiomyocytes through phosphorylation of mitochondrial hexokinase-II. Cell Death Differ 15:521–9

    Article  CAS  Google Scholar 

  • Morgan HE, Henderson MJ, Regen DM, Park CR (1961) Regulation of Glucose Uptake in Muscle. I. The effects of insulin and anoxia on glucose transport and phosphorylation in the isolated, perfused heart of normal rats. J. Biol. Chem. 236:253–261

    CAS  Google Scholar 

  • Mueckler M (1994) Facilitative glucose transporters. European Journal of Biochemistry 219:713–725

    Article  CAS  Google Scholar 

  • Murray HK, Strauss HW, Francis GB, Gerald JB, Sandy S-C, Jonathan FT, Michael LG, Robert CR (2001) In Vivo Imaging of Acute Cardiac Rejection in Human Patients Using 99mTechnetium Labeled Annexin V. In American Journal of Transplantation, pp. 270–277

  • Muzi M, Freeman SD, Burrows RC, Wiseman RW, Link JM, Krohn KA, Graham MM, Spence AM (2001) Kinetic characterization of hexokinase isoenzymes from glioma cells: Implications for FDG imaging of human brain tumors. Nuclear Medicine and Biology 28:107–116

    Article  CAS  Google Scholar 

  • Newmeyer DD, Ferguson-Miller S (2003) Mitochondria: Releasing Power for Life and Unleashing the Machineries of Death. Cell 112:481–490

    Article  CAS  Google Scholar 

  • Ng CK, Holden JE, DeGrado TR, Raffel DM, Kornguth ML, Gatley SJ (1991) Sensitivity of myocardial fluorodeoxyglucose lumped constant to glucose and insulin. American Journal of Physiology 260:H593–603

    CAS  Google Scholar 

  • Pastorino J, Hoek J (2008) Regulation of hexokinase binding to VDAC. Journal of Bioenergetics and Biomembranes 40:171–182

    Article  CAS  Google Scholar 

  • Pastorino JG, Hoek JB, Shulga N (2005) Activation of Glycogen Synthase Kinase 3{beta} Disrupts the Binding of Hexokinase II to Mitochondria by Phosphorylating Voltage-Dependent Anion Channel and Potentiates Chemotherapy-Induced Cytotoxicity. Cancer Res 65:10545–10554

    Article  CAS  Google Scholar 

  • Pastorino JG, Shulga N, Hoek JB (2002) Mitochondrial Binding of Hexokinase II Inhibits Bax-induced Cytochrome c Release and Apoptosis. J. Biol. Chem. 277:7610–7618

    Article  CAS  Google Scholar 

  • Russell RR 3rd, Bergeron R, Shulman GI, Young LH (1999) Translocation of myocardial GLUT-4 and increased glucose uptake through activation of AMPK by AICAR. American Journal of Physiology 277:H643–9

    CAS  Google Scholar 

  • Russell RR 3rd, Mrus JM, Mommessin JI, Taegtmeyer H (1992) Compartmentation of hexokinase in rat heart. A critical factor for tracer kinetic analysis of myocardial glucose metabolism. J Clin Invest 90:1972–7

    CAS  Google Scholar 

  • Santiago AP, Chaves EA, Oliveira MF, Galina A, Santiago APSA, Chaves EA, Oliveira MF, Galina A (2008) Reactive oxygen species generation is modulated by mitochondrial kinases: correlation with mitochondrial antioxidant peroxidases in rat tissues. Biochimie 90:1566–77

    Article  CAS  Google Scholar 

  • Sebastian S, Wilson JE, Mulichak A, Garavito RM (1999) Allosteric Regulation of Type I Hexokinase: A Site-Directed Mutational Study Indicating Location of the Functional Glucose 6-Phosphate Binding Site in the N-Terminal Half of the Enzyme. Archives of Biochemistry and Biophysics 362:203–210

    Article  CAS  Google Scholar 

  • Sokoloff L, Reivich M, Kennedy C, Rosiers MHD, Patlak CS, Pettigrew KD, Sakurada O, Shinohara M (1977) The 14C-deoxyglucose method for the measurement of local cerebral glucose utlisation: theory, procedure, and normal values in the conscious and anesthetised albino rat. In Journal of Neurochemistry, pp. 897–916.

  • Southworth R, Davey KA, Warley A, Garlick PB (2007) A reevaluation of the roles of hexokinase I and II in the heart. Am J Physiol Heart Circ Physiol 292:H378–86

    Article  CAS  Google Scholar 

  • Southworth R, Dearling JL, Medina RA, Flynn AA, Pedley RB, Garlick PB (2002) Dissociation of glucose tracer uptake and glucose transporter distribution in the regionally ischaemic isolated rat heart: application of a new autoradiographic technique. Eur J Nucl Med Mol Imaging 29:1334–41

    Article  CAS  Google Scholar 

  • Southworth R, Garlick PB (2003) Dobutamine responsiveness, PET mismatch, and lack of necrosis in low-flow ischemia: is this hibernation in the isolated rat heart? Am J Physiol Heart Circ Physiol 285:H316–24

    CAS  Google Scholar 

  • Southworth R, Parry CR, Parkes HG, Medina RA, Garlick PB (2003) Tissue-specific differences in 2-fluoro-2-deoxyglucose metabolism beyond FDG-6-P: a 19F NMR spectroscopy study in the rat. In NMR in Biomedicine, pp. 494–502.

  • Stanley WC, Recchia FA, Lopaschuk GD (2005) Myocardial Substrate Metabolism in the Normal and Failing Heart. Physiol. Rev. 85:1093–1129

    Article  CAS  Google Scholar 

  • Sui D, Wilson JE (1997) Structural Determinants for the Intracellular Localization of the Isozymes of Mammalian Hexokinase: Intracellular Localization of Fusion Constructs Incorporating Structural Elements from the Hexokinase Isozymes and the Green Fluorescent Protein. Archives of Biochemistry and Biophysics 345:111–125

    Article  CAS  Google Scholar 

  • Tian R, Abel ED (2001) Responses of GLUT4-Deficient Hearts to Ischemia Underscore the Importance of Glycolysis. Circulation 103:2961–2966

    CAS  Google Scholar 

  • Underwood SR, Bax JJ, v Dahl J, Henein MY, van Rossum AC, Schwarz ER, Vanoverschelde J-L, v d Wall EE, Wijns W (2004) Imaging techniques for the assessment of myocardial hibernation: Report of a Study Group of the European Society of Cardiology. Eur Heart J 25:815–836

    Article  Google Scholar 

  • Vogt C, Yki-Jarvinen H, Iozzo P, Pipek R, Pendergrass M, Koval J, Ardehali H, Printz R, Granner D, DeFronzo R et al (1998) Effects of Insulin on Subcellular Localization of Hexokinase II in Human Skeletal Muscle in Vivo. J Clin Endocrinol Metab 83:230–234

    Article  CAS  Google Scholar 

  • Wilson JE (2003) Isozymes of mammalian hexokinase: structure, subcellular localization and metabolic function. J Exp Biol 206:2049–2057

    Article  CAS  Google Scholar 

  • Zaha V, Nitschke R, Gobel H, Fischer-Rasokat U, Zechner C, Doenst T (2005) Discrepancy between GLUT4 translocation and glucose uptake after ischemia. Mol Cell Biochem 278:129–37

    Article  CAS  Google Scholar 

  • Zuurbier CJ, Eerbeek O, Meijer AJ (2005) Ischemic preconditioning, insulin, and morphine all cause hexokinase redistribution. Am J Physiol Heart Circ Physiol 289:H496–9

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Imaging Sciences, King’s College London, The Rayne Institute, St. Thomas’ Hospital, Lambeth Palace Rd, London, SE1 7EH, UK

    Richard Southworth

Authors
  1. Richard Southworth
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Richard Southworth.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Southworth, R. Hexokinase-mitochondrial interaction in cardiac tissue: implications for cardiac glucose uptake, the 18FDG lumped constant and cardiac protection. J Bioenerg Biomembr 41, 187–193 (2009). https://doi.org/10.1007/s10863-009-9207-9

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10863-009-9207-9

Keywords

Search

Navigation