Journal of Bioenergetics and Biomembranes

, Volume 46, Issue 1, pp 17–31 | Cite as

Comparative analysis of some aspects of mitochondrial metabolism in differentiated and undifferentiated neuroblastoma cells

  • Aleksandr Klepinin
  • Vladimir Chekulayev
  • Natalja Timohhina
  • Igor Shevchuk
  • Kersti Tepp
  • Andrus Kaldma
  • Andre Koit
  • Valdur Saks
  • Tuuli Kaambre


The aim of the present study is to clarify some aspects of the mechanisms of regulation of mitochondrial metabolism in neuroblastoma (NB) cells. Experiments were performed on murine Neuro-2a (N2a) cell line, and the same cells differentiated by all-trans-retinoic acid (dN2a) served as in vitro model of normal neurons. Oxygraphy and Metabolic Control Analysis (MCA) were applied to characterize the function of mitochondrial oxidative phosphorylation (OXPHOS) in NB cells. Flux control coefficients (FCCs) for components of the OXPHOS system were determined using titration studies with specific non-competitive inhibitors in the presence of exogenously added ADP. Respiration rates of undifferentiated Neuro-2a cells (uN2a) and the FCC of Complex-II in these cells were found to be considerably lower than those in dN2a cells. Our results show that NB is not an exclusively glycolytic tumor and could produce a considerable part of ATP via OXPHOS. Two important enzymes - hexokinase-2 and adenylate kinase-2 can play a role in the generation of ATP in NB cells. MCA has shown that in uN2a cells the key sites in the regulation of OXPHOS are complexes I, II and IV, whereas in dN2a cells complexes II and IV. Results obtained for the phosphate and adenine nucleotide carriers showed that in dN2a cells these carriers exerted lower control over the OXPHOS than in undifferentiated cells. The sum of FCCs for both types of NB cells was found to exceed significantly that for normal cells suggesting that in these cells the respiratory chain was somehow reorganized or assembled into large supercomplexes.


Energy metabolism Metabolic control analysis Neuroblastoma Adenylate kinase Hexokinase Warburg effect 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Almeida A, Bolaños JP, Moncada S (2010) E3 ubiquitin ligase APC/C-Cdh1 accounts for the Warburg effect by linking glycolysis to cell proliferation. Proc Natl Acad Sci 107(2):738–741. doi: 10.1073/pnas.0913668107 CrossRefGoogle Scholar
  2. Ames A (2000) CNS energy metabolism as related to function. Brain Res Rev 34(1–2):42–68. doi: 10.1016/S0165-0173(00)00038-2 CrossRefGoogle Scholar
  3. Anmann T, Guzun R, Beraud N, Pelloux S, Kuznetsov AV, Kogerman L et al (2006) Different kinetics of the regulation of respiration in permeabilized cardiomyocytes and in HL-1 cardiac cells. Importance of cell structure/organization for respiration regulation. Biochim Biophys Acta 1757(12):1597–1606. doi: 10.1016/j.bbabio.2006.09.008 CrossRefGoogle Scholar
  4. Apte SP, Sarangarajan R (2008) Cellular respiration and carcinogenesis. Springer, New YorkGoogle Scholar
  5. Astuti D, Hart-Holden N, Latif F, Lalloo F, Black GC, Lim C et al (2003) Genetic analysis of mitochondrial complex II subunits SDHD, SDHB and SDHC in paraganglioma and phaeochromocytoma susceptibility. Clinical Endocrinology 59(6):728–733. doi: 10.1046/j.1365-2265.2003.01914.x CrossRefGoogle Scholar
  6. Astuti D, Morris M, Krona C, Abel F, Gentle D, Martinsson T et al (2004) Investigation of the role of SDHB inactivation in sporadic phaeochromocytoma and neuroblastoma. Br J Cancer 91(10):1835–1841CrossRefGoogle Scholar
  7. Atsumi T, Chesney J, Metz C, Leng L, Donnelly S, Makita Z et al (2002) High expression of inducible 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (iPFK-2; PFKFB3) in human cancers. Cancer Res 62(20):5881–5887Google Scholar
  8. Bardella C, Pollard PJ, Tomlinson I (2011) SDH mutations in cancer. Biochim Biophys Acta (BBA) Bioenerg 1807(11):1432–1443. doi: 10.1016/j.bbabio.2011.07.003 CrossRefGoogle Scholar
  9. Beemer FA, Vlug AM, Rousseau-Merck MF, van Veelen CW, Rijksen G, Staal GE (1984) Glycolytic enzymes from human neuroectodermal tumors of childhood. Eur J Cancer Clin Oncol 20(2):253–259CrossRefGoogle Scholar
  10. Biswas S, Ray M, Misra S, Dutta DP, Ray S (1997) Selective inhibition of mitochondrial respiration and glycolysis in human leukaemic leucocytes by methylglyoxal. Biochem J 323(Pt 2):343–348Google Scholar
  11. Blanco V, Lopez Camelo J, Carri NG (2001) Growth inhibition, morphological differentiation and stimulation of survival in neuronal cell type (Neuro-2a) treated with trophic molecules. Cell Biol Int 25(9):909–917CrossRefGoogle Scholar
  12. Bonora E, Porcelli AM, Gasparre G, Biondi A, Ghelli A, Carelli V et al (2006) Defective oxidative phosphorylation in thyroid oncocytic carcinoma is associated with pathogenic mitochondrial DNA mutations affecting complexes I and III. Cancer Res 66(12):6087–6096. doi: 10.1158/0008-5472.CAN-06-0171 CrossRefGoogle Scholar
  13. Bustamante E, Pedersen PL (1977) High aerobic glycolysis of rat hepatoma cells in culture: Role of mitochondrial hexokinase. Proc Natl Acad Sci 74(9):3735–3739CrossRefGoogle Scholar
  14. Bustamante E, Pedersen PL (1980) Mitochondrial hexokinase of rat hepatoma cells in culture: solubilization and kinetic properties. Biochemistry 19(22):4972–4977CrossRefGoogle Scholar
  15. Cascon A, Landa I, Lopez-Jimenez E, Diez-Hernandez A, Buchta M, Montero-Conde C et al (2008) Molecular characterisation of a common SDHB deletion in paraganglioma patients. J Med Genet 45(4):233–238. doi: 10.1136/jmg.2007.054965 CrossRefGoogle Scholar
  16. Chen Z, Zhang H, Lu W, Huang P (2009) Role of mitochondria-associated hexokinase II in cancer cell death induced by 3-bromopyruvate. Biochim Biophys Acta (BBA) Bioenerg 1787(5):553–560. doi: 10.1016/j.bbabio.2009.03.003 CrossRefGoogle Scholar
  17. Chevrollier A, Loiseau D, Chabi B, Renier G, Douay O, Malthiery Y et al (2005) ANT2 isoform required for cancer cell glycolysis. J Bioenerg Biomembr 37(5):307–316. doi: 10.1007/s10863-005-8642-5 CrossRefGoogle Scholar
  18. Chevrollier A, Loiseau D, Reynier P, Stepien G (2011) Adenine nucleotide translocase 2 is a key mitochondrial protein in cancer metabolism. Biochim Biophys Acta (BBA) Bioenerg 1807(6):562–567. doi: 10.1016/j.bbabio.2010.10.008 CrossRefGoogle Scholar
  19. Chuang J-H, Chou M-H, Tai M-H, Lin T-K, Liou C-W, Chen T et al (2013) 2-Deoxyglucose treatment complements the cisplatin- or BH3-only mimetic-induced suppression of neuroblastoma cell growth. Int J Biochem Cell Biol 45(5):944–951. doi: 10.1016/j.biocel.2013.01.019 CrossRefGoogle Scholar
  20. de Bruin W, Oerlemans F, Wieringa B (2004) Adenylate kinase I does not affect cellular growth characteristics under normal and metabolic stress conditions. Experimental Cell Research 297(1):97–107. doi: 10.1016/j.yexcr.2004.02.025 CrossRefGoogle Scholar
  21. Deubzer B, Mayer F, Kuci Z, Niewisch M, Merkel G, Handgretinger R et al (2010) H(2)O(2)-mediated cytotoxicity of pharmacologic ascorbate concentrations to neuroblastoma cells: potential role of lactate and ferritin. Cell Physiol Biochem 25(6):767–774. doi: 10.1159/000315098 CrossRefGoogle Scholar
  22. Dolce V, Scarcia P, Iacopetta D, Palmieri F (2005) A fourth ADP/ATP carrier isoform in man: identification, bacterial expression, functional characterization and tissue distribution. FEBS Lett 579(3):633–637. doi: 10.1016/j.febslet.2004.12.034 CrossRefGoogle Scholar
  23. Dzeja PP, Terzic A (2003) Phosphotransfer networks and cellular energetics. J Exp Biol 206(Pt 12):2039–2047CrossRefGoogle Scholar
  24. Dzeja P, Terzic A (2009) Adenylate kinase and AMP signaling networks: Metabolic monitoring, signal communication and body energy sensing. Int J Mol Sci 10(4):1729–1772. doi: 10.3390/ijms10041729 CrossRefGoogle Scholar
  25. Dzeja PP, Vitkevicius KT, Redfield MM, Burnett JC, Terzic A (1999) Adenylate kinase-catalyzed phosphotransfer in the myocardium : increased contribution in heart failure. Circ Res 84(10):1137–1143CrossRefGoogle Scholar
  26. Ellman GL, Courtney KD, Andres V Jr, Feather-Stone RM (1961) A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharmacol 7:88–95CrossRefGoogle Scholar
  27. Feichtinger R, Zimmermann F, Mayr J, Neureiter D, Hauser-Kronberger C, Schilling F et al (2010) Low aerobic mitochondrial energy metabolism in poorly- or undifferentiated neuroblastoma. BMC Cancer 10(1):149CrossRefGoogle Scholar
  28. Fell D (1997) Understanding the control of metabolism. Portland Press, LondonGoogle Scholar
  29. Fell D (2005) Metabolic Control Analysis. In (pp. 69–80).Google Scholar
  30. Gatenby RA, Gillies RJ (2004) Why do cancers have high aerobic glycolysis? Nat Rev Cancer 4(11):891–899. doi: 10.1038/nrc1478 CrossRefGoogle Scholar
  31. Geschwind JF, Georgiades CS, Ko YH, Pedersen PL (2004) Recently elucidated energy catabolism pathways provide opportunities for novel treatments in hepatocellular carcinoma. Expert Rev Anticancer Ther 4(3):449–457. doi: 10.1586/14737140.4.3.449 CrossRefGoogle Scholar
  32. Gogvadze V, Orrenius S, Zhivotovsky B (2009) Mitochondria as targets for cancer chemotherapy. Seminars in Cancer Biology 19(1):57–66. doi: 10.1016/j.semcancer.2008.11.007 CrossRefGoogle Scholar
  33. Groen AK, Wanders RJ, Westerhoff HV, van der Meer R, Tager JM (1982) Quantification of the contribution of various steps to the control of mitochondrial respiration. J Biol Chem 257(6):2754–2757Google Scholar
  34. Guzun R, Timohhina N, Tepp K, Monge C, Kaambre T, Sikk P et al (2009) Regulation of respiration controlled by mitochondrial creatine kinase in permeabilized cardiac cells in situ. Importance of system level properties. Biochim Biophys Acta 1787(9):1089–1105. doi: 10.1016/j.bbabio.2009.03.024 CrossRefGoogle Scholar
  35. Guzun R, Karu-Varikmaa M, Gonzalez-Granillo M, Kuznetsov AV, Michel L, Cottet-Rousselle C et al (2011) Mitochondria-cytoskeleton interaction: Distribution of beta-tubulins in cardiomyocytes and HL-1 cells. Biochim Biophys Acta 1807(4):458–469. doi: 10.1016/j.bbabio.2011.01.010 CrossRefGoogle Scholar
  36. Hamburg RJ, Friedman DL, Olson EN, Ma TS, Cortez MD, Goodman C et al (1990) Muscle creatine kinase isoenzyme expression in adult human brain. J Biol Chem 265(11):6403–6409Google Scholar
  37. Hoefs SJG, Rodenburg RJ, Smeitink JAM, van den Heuvel LP (2012) Molecular base of biochemical complex I deficiency. Mitochondrion 12(5):520–532. doi: 10.1016/j.mito.2012.07.106 CrossRefGoogle Scholar
  38. Huang LS, Sun G, Cobessi D, Wang AC, Shen JT, Tung EY et al (2006) 3-nitropropionic acid is a suicide inhibitor of mitochondrial respiration that, upon oxidation by complex II, forms a covalent adduct with a catalytic base arginine in the active site of the enzyme. J Biol Chem 281(9):5965–5972. doi: 10.1074/jbc.M511270200 CrossRefGoogle Scholar
  39. Ihrlund LS, Hernlund E, Khan O, Shoshan MC (2008) 3-Bromopyruvate as inhibitor of tumour cell energy metabolism and chemopotentiator of platinum drugs. Mol Oncol 2(1):94–101CrossRefGoogle Scholar
  40. Ishiguro Y, Kato K, Akatsuka H, Ito T (1990) The diagnostic and prognostic value of pretreatment serum creatine kinase BB levels in patients with neuroblastoma. Cancer 65(9):2014–2019CrossRefGoogle Scholar
  41. Kaambre T, Chekulayev V, Shevchuk I, Karu-Varikmaa M, Timohhina N, Tepp K et al (2012a) Metabolic control analysis of cellular respiration in situ in intraoperational samples of human breast cancer. J Bioenerg Biomembr 44(5):539–558. doi: 10.1007/s10863-012-9457-9 CrossRefGoogle Scholar
  42. Kaambre T, Chekulayev V, Shevchuk I, Karu-Varikmaa M, Timohhina N, Tepp K et al (2012b) Metabolic control analysis of cellular respiration in situ in intraoperational samples of human breast cancer. J Bioenerg Biomembr. doi: 10.1007/s10863-012-9457-9 Google Scholar
  43. Kholodenko BN, Westerhoff HV (1993) Metabolic channelling and control of the flux. FEBS Lett 320(1):71–74CrossRefGoogle Scholar
  44. Krieger-Hinck N, Gustke H, Valentiner U, Mikecz P, Buchert R, Mester J et al (2006) Visualisation of neuroblastoma growth in a Scid mouse model using [18F]FDG and [18F]FLT-PET. Anticancer Res 26(5A):3467–3472Google Scholar
  45. Krieglstein J, Mwasekaga S (1987) Effect of methohexital on the relationship between hexokinase distribution and energy metabolism in neuroblastoma cells. Arzneimittelforschung 37(3):291–295Google Scholar
  46. Krieglstein J, Schachtschabel DO, Wever K, Wickop G (1981) Influence of thiopental on intracellular distribution of hexokinase activity in various tumor cells. Arzneimittelforschung 31(1):121–123Google Scholar
  47. Kuznetsov AV, Veksler V, Gellerich FN, Saks V, Margreiter R, Kunz WS (2008) Analysis of mitochondrial function in situ in permeabilized muscle fibers, tissues and cells. Nat Protoc 3(6):965–976. doi: 10.1038/nprot.2008.61 CrossRefGoogle Scholar
  48. Le Bras M, Borgne-Sanchez A, Touat Z, El Dein OS, Deniaud A, Maillier E et al (2006) Chemosensitization by knockdown of adenine nucleotide translocase-2. Cancer Res 66(18):9143–9152. doi: 10.1158/0008-5472.CAN-05-4407 CrossRefGoogle Scholar
  49. Lenaz G, Genova ML (2009) Structural and functional organization of the mitochondrial respiratory chain: a dynamic super-assembly. Int J Biochem Cell Biol 41(10):1750–1772CrossRefGoogle Scholar
  50. Lenaz G, Genova ML (2010) Structure and organization of mitochondrial respiratory complexes: a new understanding of an old subject. Antioxid Redox Signal 12(8):961–1008. doi: 10.1089/ars.2009.2704 CrossRefGoogle Scholar
  51. Levy A, Zage P, Akers L, Ghisoli M, Chen Z, Fang W et al (2012) The combination of the novel glycolysis inhibitor 3-BrOP and rapamycin is effective against neuroblastoma. Investigational New Drugs 30(1):191–199. doi: 10.1007/s10637-010-9551-y CrossRefGoogle Scholar
  52. Lienhard GE, Secemski II (1973) P 1, P 5 -Di(adenosine-5′)pentaphosphate, a potent multisubstrate inhibitor of adenylate kinase. J Biol Chem 248(3):1121–1123Google Scholar
  53. Majewski N, Nogueira V, Bhaskar P, Coy PE, Skeen JE, Gottlob K et al (2004) Hexokinase-mitochondria interaction mediated by Akt is required to inhibit apoptosis in the presence or absence of Bax and Bak. Mol Cell 16(5):819–830. doi: 10.1016/j.molcel.2004.11.014 CrossRefGoogle Scholar
  54. Marin-Hernandez A, Rodriguez-Enriquez S, Vital-Gonzalez PA, Flores-Rodriguez FL, Macias-Silva M, Sosa-Garrocho M et al (2006) Determining and understanding the control of glycolysis in fast-growth tumor cells. Flux control by an over-expressed but strongly product-inhibited hexokinase. FEBS J 273(9):1975–1988. doi: 10.1111/j.1742-4658.2006.05214.x CrossRefGoogle Scholar
  55. Mathupala SP, Ko YH, Pedersen PL (2006) Hexokinase II: cancer's double-edged sword acting as both facilitator and gatekeeper of malignancy when bound to mitochondria. Oncogene 25(34):4777–4786. doi: 10.1038/sj.onc.1209603 CrossRefGoogle Scholar
  56. Matsushita K, Uchida K, Saigusa S, Ide S, Hashimoto K, Koike Y et al (2012) Glycolysis inhibitors as a potential therapeutic option to treat aggressive neuroblastoma expressing GLUT1. Journal of Pediatric Surgery 47(7):1323–1330. doi: 10.1016/j.jpedsurg.2011.12.007 CrossRefGoogle Scholar
  57. Monge C, Beraud N, Kuznetsov A, Rostovtseva T, Sackett D, Schlattner U et al (2008) Regulation of respiration in brain mitochondria and synaptosomes: restrictions of ADP diffusion in situ, roles of tubulin, and mitochondrial creatine kinase. Mol Cell Biochem 318(1–2):147–165. doi: 10.1007/s11010-008-9865-7 CrossRefGoogle Scholar
  58. Monge C, Beraud N, Tepp K, Pelloux S, Chahboun S, Kaambre T et al (2009) Comparative analysis of the bioenergetics of adult cardiomyocytes and nonbeating HL-1 cells: respiratory chain activities, glycolytic enzyme profiles, and metabolic fluxes. Can J Physiol Pharmacol 87(4):318–326. doi: 10.1139/y09-018 CrossRefGoogle Scholar
  59. Moreno-Sanchez R, Rodriguez-Enriquez S, Marin-Hernandez A, Saavedra E (2007) Energy metabolism in tumor cells. FEBS J 274(6):1393–1418. doi: 10.1111/j.1742-4658.2007.05686.x CrossRefGoogle Scholar
  60. Moreno-Sanchez R, Saavedra E, Rodriguez-Enriquez S, Olin-Sandoval V (2008) Metabolic control analysis: a tool for designing strategies to manipulate metabolic pathways. J Biomed Biotechnol 2008:597913. doi: 10.1155/2008/597913 CrossRefGoogle Scholar
  61. Moreno-Sánchez R, Rodríguez-Enríquez S, Saavedra E, Marín-Hernández A, Gallardo-Pérez JC (2009) The bioenergetics of cancer: Is glycolysis the main ATP supplier in all tumor cells? BioFactors 35(2):209–225. doi: 10.1002/biof.31 CrossRefGoogle Scholar
  62. Moreno-Sanchez R, Saavedra E, Rodriguez-Enriquez S, Gallardo-Perez JC, Quezada H, Westerhoff HV (2010) Metabolic control analysis indicates a change of strategy in the treatment of cancer. Mitochondrion 10(6):626–639. doi: 10.1016/j.mito.2010.06.002 CrossRefGoogle Scholar
  63. Nakashima RA, Paggi MG, Scott LJ, Pedersen PL (1988) Purification and characterization of a bindable form of mitochondrial bound hexokinase from the highly glycolytic AS-30D rat hepatoma cell line. Cancer Res 48(4):913–919Google Scholar
  64. Neary JT, Rathbone MP, Cattabeni F, Abbracchio MP, Burnstock G (1996) Trophic actions of extracellular nucleotides and nucleosides on glial and neuronal cells. Trends Neurosci 19(1):13–18CrossRefGoogle Scholar
  65. Patra S, Bera S, SinhaRoy S, Ghoshal S, Ray S, Basu A et al (2008) Progressive decrease of phosphocreatine, creatine and creatine kinase in skeletal muscle upon transformation to sarcoma. FEBS J 275(12):3236–3247. doi: 10.1111/j.1742-4658.2008.06475.x CrossRefGoogle Scholar
  66. Patra S, Ghosh A, Roy SS, Bera S, Das M, Talukdar D et al (2012) A short review on creatine-creatine kinase system in relation to cancer and some experimental results on creatine as adjuvant in cancer therapy. Amino Acids 42(6):2319–2330. doi: 10.1007/s00726-011-0974-3 CrossRefGoogle Scholar
  67. Pedersen PL (1978) Tumor mitochondria and the bioenergetics of cancer cells. Prog Exp Tumor Res 22:190–274Google Scholar
  68. Pedersen PL (2007a) The cancer cell's "power plants" as promising therapeutic targets: an overview. J Bioenerg Biomembr 39(1):1–12. doi: 10.1007/s10863-007-9070-5 CrossRefGoogle Scholar
  69. Pedersen PL (2007b) Warburg, me and Hexokinase 2: Multiple discoveries of key molecular events underlying one of cancers' most common phenotypes, the "Warburg Effect", i.e., elevated glycolysis in the presence of oxygen. J Bioenerg Biomembr 39(3):211–222. doi: 10.1007/s10863-007-9094-x CrossRefGoogle Scholar
  70. Pedersen PL (2008) Voltage dependent anion channels (VDACs): a brief introduction with a focus on the outer mitochondrial compartment's roles together with hexokinase-2 in the "Warburg effect" in cancer. J Bioenerg Biomembr 40(3):123–126. doi: 10.1007/s10863-008-9165-7 CrossRefGoogle Scholar
  71. Pedersen PL (2012) 3-bromopyruvate (3BP) a fast acting, promising, powerful, specific, and effective "small molecule" anti-cancer agent taken from labside to bedside: introduction to a special issue. J Bioenerg Biomembr 44(1):1–6. doi: 10.1007/s10863-012-9425-4 CrossRefGoogle Scholar
  72. Pedersen PL, Mathupala S, Rempel A, Geschwind JF, Ko YH (2002) Mitochondrial bound type II hexokinase: a key player in the growth and survival of many cancers and an ideal prospect for therapeutic intervention. Biochim Biophys Acta (BBA) Bioenerg 1555(1–3):14–20. doi: 10.1016/S0005-2728(02)00248-7 CrossRefGoogle Scholar
  73. Puurand M, Peet N, Piirsoo A, Peetsalu M, Soplepmann J, Sirotkina M et al (2012) Deficiency of the complex I of the mitochondrial respiratory chain but improved adenylate control over succinate-dependent respiration are human gastric cancer-specific phenomena. Mol Cell Biochem 370(1–2):69–78. doi: 10.1007/s11010-012-1399-3 CrossRefGoogle Scholar
  74. Rostovtseva TK, Sheldon KL, Hassanzadeh E, Monge C, Saks V, Bezrukov SM et al (2008) Tubulin binding blocks mitochondrial voltage-dependent anion channel and regulates respiration. Proc Natl Acad Sci USA 105(48):18746–18751. doi: 10.1073/pnas.0806303105 CrossRefGoogle Scholar
  75. Saks VA, Belikova YO, Kuznetsov AV (1991) In vivo regulation of mitochondrial respiration in cardiomyocytes: specific restrictions for intracellular diffusion of ADP. Biochim Biophys Acta 1074(2):302–311CrossRefGoogle Scholar
  76. Saks VA, Veksler VI, Kuznetsov AV, Kay L, Sikk P, Tiivel T et al (1998) Permeabilized cell and skinned fiber techniques in studies of mitochondrial function in vivo. Mol Cell Biochem 184(1–2):81–100CrossRefGoogle Scholar
  77. Saks V, Kuznetsov A, Andrienko T, Usson Y, Appaix F, Guerrero K et al (2003) Heterogeneity of ADP diffusion and regulation of respiration in cardiac cells. Biophys J 84(5):3436–3456. doi: 10.1016/S0006-3495(03)70065-4 CrossRefGoogle Scholar
  78. Sato C, Matsuda T, Kitajima K (2002) Neuronal Differentiation-dependent Expression of the Disialic Acid Epitope on CD166 and Its Involvement in Neurite Formation in Neuro2A Cells. J Biol Chem 277(47):45299–45305. doi: 10.1074/jbc.M206046200 CrossRefGoogle Scholar
  79. Schimke RN, Collins DL, Stolle CA (2010) Paraganglioma, neuroblastoma, and a SDHB mutation: Resolution of a 30-year-old mystery. Am J Med Genet A 152A(6):1531–1535. doi: 10.1002/ajmg.a.33384 Google Scholar
  80. Seppet EK, Kaambre T, Sikk P, Tiivel T, Vija H, Tonkonogi M et al (2001) Functional complexes of mitochondria with Ca, MgATPases of myofibrils and sarcoplasmic reticulum in muscle cells. Biochim Biophys Acta 1504(2–3):379–395CrossRefGoogle Scholar
  81. Seppet EK, Eimre M, Anmann T, Seppet E, Piirsoo A, Peet N et al (2006) Structure-function relationships in the regulation of energy transfer between mitochondria and ATPases in cardiac cells. Exp Clin Cardiol 11(3):189–194Google Scholar
  82. Sharma LK, Fang H, Liu J, Vartak R, Deng J, Bai Y (2011) Mitochondrial respiratory complex I dysfunction promotes tumorigenesis through ROS alteration and AKT activation. Hum Mol Genet 20(23):4605–4616. doi: 10.1093/hmg/ddr395 CrossRefGoogle Scholar
  83. Simonnet H, Demont J, Pfeiffer K, Guenaneche L, Bouvier R, Brandt U et al (2003) Mitochondrial complex I is deficient in renal oncocytomas. Carcinogenesis 24(9):1461–1466. doi: 10.1093/carcin/bgg109 CrossRefGoogle Scholar
  84. Stepien G, Torroni A, Chung AB, Hodge JA, Wallace DC (1992) Differential expression of adenine nucleotide translocator isoforms in mammalian tissues and during muscle cell differentiation. J Biol Chem 267(21):14592–14597Google Scholar
  85. Tepp K, Timohhina N, Chekulayev V, Shevchuk I, Kaambre T, Saks V (2010) Metabolic control analysis of integrated energy metabolism in permeabilized cardiomyocytes - experimental study. Acta Biochim Pol 57(4):421–430Google Scholar
  86. Tepp K, Shevchuk I, Chekulayev V, Timohhina N, Kuznetsov AV, Guzun R et al (2011) High efficiency of energy flux controls within mitochondrial interactosome in cardiac intracellular energetic units. Biochim Biophys Acta Bioenerg 1807(12):1549–1561. doi: 10.1016/j.bbabio.2011.08.005 CrossRefGoogle Scholar
  87. Tsung SH (1976) Creatine kinase isoenzyme patterns in human tissue obtained at surgery. Clin Chem 22(2):173–175Google Scholar
  88. Warburg O (1956) On respiratory impairment in cancer cells. Science 124(3215):269–270Google Scholar
  89. Whitaker-Menezes D, Martinez-Outschoorn UE, Lin Z, Ertel A, Flomenberg N, Witkiewicz AK et al (2011) Evidence for a stromal-epithelial "lactate shuttle" in human tumors: MCT4 is a marker of oxidative stress in cancer-associated fibroblasts. Cell Cycle 10(11):1772–1783CrossRefGoogle Scholar
  90. Xu R-h, Pelicano H, Zhou Y, Carew JS, Feng L, Bhalla KN et al (2005) Inhibition of Glycolysis in Cancer Cells: A Novel Strategy to Overcome Drug Resistance Associated with Mitochondrial Respiratory Defect and Hypoxia. Cancer Res 65(2):613–621Google Scholar
  91. Xun Z, Lee DY, Lim J, Canaria CA, Barnebey A, Yanonne SM et al (2012) Retinoic acid-induced differentiation increases the rate of oxygen consumption and enhances the spare respiratory capacity of mitochondria in SH-SY5Y cells. Mech Ageing Dev 133(4):176–185. doi: 10.1016/j.mad.2012.01.008 CrossRefGoogle Scholar
  92. Zamora M, Granell M, Mampel T, Vinas O (2004) Adenine nucleotide translocase 3 (ANT3) overexpression induces apoptosis in cultured cells. FEBS Lett 563(1–3):155–160. doi: 10.1016/S0014-5793(04)00293-5 CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Aleksandr Klepinin
    • 1
  • Vladimir Chekulayev
    • 1
  • Natalja Timohhina
    • 1
  • Igor Shevchuk
    • 1
  • Kersti Tepp
    • 1
  • Andrus Kaldma
    • 1
    • 3
  • Andre Koit
    • 1
    • 3
  • Valdur Saks
    • 1
    • 2
  • Tuuli Kaambre
    • 1
    • 4
  1. 1.Laboratory of BioenergeticsNational Institute of Chemical Physics and BiophysicsTallinnEstonia
  2. 2.Laboratory of Fundamental and Applied BioenergeticsJoseph Fourier UniversityGrenobleFrance
  3. 3.Department of Gene TechnologyTallinn University of TechnologyTallinnEstonia
  4. 4.Institute of Mathematics and Natural SciencesTallinn UniversityTallinnEstonia

Personalised recommendations