Skip to main content

Advertisement

SpringerLink
Log in

Changes in the mitochondrial function and in the efficiency of energy transfer pathways during cardiomyocyte aging

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

The role of mitochondria in alterations that take place in the muscle cell during healthy aging is a matter of debate during recent years. Most of the studies in bioenergetics have a focus on the model of isolated mitochondria, while changes in the crosstalk between working myofibrils and mitochondria in senescent cardiomyocytes have been less studied. The aim of our research was to investigate the modifications in the highly regulated ATP production and energy transfer systems in heart cells in old rat cardiomyocytes. The results of our work demonstrated alterations in the diffusion restrictions of energy metabolites, manifested by changes in the apparent Michaelis–Menten constant of mitochondria to exogenous ADP. The creatine kinase (CK) phosphotransfer pathway efficiency declines significantly in senescence. The ability of creatine to stimulate OXPHOS as well as to increase the affinity of mitochondria for ADP is falling and the most critical decline is already in the 1-year group (middle-age model in rats). Also, a moderate decrease in the adenylate kinase phosphotransfer system was detected. The importance of glycolysis increases in senescence, while the hexokinase activity does not change during healthy aging. The main result of our study is that the decline in the heart muscle performance is not caused by the changes in the respiratory chain complexes activity but mainly by the decrease in the energy transfer efficiency, especially by the CK pathway.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Abbreviations

AK:

Adenylate kinase

ANT:

Adenine nucleotide translocase

CI–IV:

Respiratory chain complexes I–IV, respectively

CM:

Cardiomyocyte

CK:

Creatine kinase

HK:

Hexokinase

ICEU:

Intracellular energetic unit

MI:

Mitochondrial interactosome

MOM:

Mitochondrial outer membrane

MtCK:

Mitochondrial creatine kinase

OXPHOS:

Oxidative phosphorylation

PCr:

Phosphocreatine

RC:

Respiratory chain

RCC:

Respiratory chain complex

ROS:

Reactive oxygen species

VDAC:

Voltage-dependent anion channel

References

  1. Lakatta EG (2015) So! What’s aging? Is cardiovascular aging a disease? J Mol Cell Cardiol 83:1–13. doi:10.1016/j.yjmcc.2015.04.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Olivetti G, Melissari M, Capasso JM, Anversa P (1991) Cardiomyopathy of the aging human heart. Myocyte loss and reactive cellular hypertrophy. Circ Res 68(6):1560–1568

    Article  CAS  PubMed  Google Scholar 

  3. Bergmann O, Bhardwaj RD, Bernard S, Zdunek S, Barnabe-Heider F, Walsh S, Zupicich J, Alkass K, Buchholz BA, Druid H, Jovinge S, Frisen J (2009) Evidence for cardiomyocyte renewal in humans. Science 324(5923):98–102. doi:10.1126/science.1164680

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Bergmann O, Zdunek S, Felker A, Salehpour M, Alkass K, Bernard S, Sjostrom SL, Szewczykowska M, Jackowska T, Dos Remedios C, Malm T, Andra M, Jashari R, Nyengaard JR, Possnert G, Jovinge S, Druid H, Frisen J (2015) Dynamics of cell generation and turnover in the human heart. Cell 161(7):1566–1575. doi:10.1016/j.cell.2015.05.026

    Article  CAS  PubMed  Google Scholar 

  5. Senyo SE, Steinhauser ML, Pizzimenti CL, Yang VK, Cai L, Wang M, Wu TD, Guerquin-Kern JL, Lechene CP, Lee RT (2013) Mammalian heart renewal by pre-existing cardiomyocytes. Nature 493(7432):433–436. doi:10.1038/nature11682

    Article  CAS  PubMed  Google Scholar 

  6. Wei YH, Wu SB, Ma YS, Lee HC (2009) Respiratory function decline and DNA mutation in mitochondria, oxidative stress and altered gene expression during aging. Chang Gung Med J 32(2):113–132

    PubMed  Google Scholar 

  7. Troen BR (2003) The biology of aging. Mt Sinai J Med 70(1):3–22

    PubMed  Google Scholar 

  8. Seppet E, Gruno M, Peetsalu A, Gizatullina Z, Nguyen HP, Vielhaber S, Wussling MH, Trumbeckaite S, Arandarcikaite O, Jerzembeck D, Sonnabend M, Jegorov K, Zierz S, Striggow F, Gellerich FN (2009) Mitochondria and energetic depression in cell pathophysiology. Int J Mol Sci 10(5):2252–2303. doi:10.3390/ijms10052252

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Lopez-Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G (2013) The hallmarks of aging. Cell 153(6):1194–1217. doi:10.1016/j.cell.2013.05.039

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Tepp K, Timohhina N, Puurand M, Klepinin A, Chekulayev V, Shevchuk I, Kaambre T (2016) Bioenergetics of the aging heart and skeletal muscles: modern concepts and controversies. Ageing Res Rev 28:1–14. doi:10.1016/j.arr.2016.04.001

    Article  CAS  PubMed  Google Scholar 

  11. Yaniv Y, Juhaszova M, Sollott SJ (2013) Age-related changes of myocardial ATP supply and demand mechanisms. Trends Endocrinol Metab 24(10):495–505. doi:10.1016/j.tem.2013.06.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Wang Y, Hekimi S (2015) Mitochondrial dysfunction and longevity in animals: untangling the knot. Science 350(6265):1204–1207. doi:10.1126/science.aac4357

    Article  CAS  PubMed  Google Scholar 

  13. Payne BA, Chinnery PF (2015) Mitochondrial dysfunction in aging: much progress but many unresolved questions. Biochim Biophys Acta 1847(11):1347–1353. doi:10.1016/j.bbabio.2015.05.022

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Williamson JR, Ford C, Illingworth J, Safer B (1976) Coordination of citric acid cycle activity with electron transport flux. Circ Res 38(5 Suppl 1):I39–I51

    CAS  PubMed  Google Scholar 

  15. Balaban RS (2002) Cardiac energy metabolism homeostasis: role of cytosolic calcium. J Mol Cell Cardiol 34(10):1259–1271

    Article  CAS  PubMed  Google Scholar 

  16. Ventura-Clapier R, Garnier A, Veksler V, Joubert F (2011) Bioenergetics of the failing heart. Biochim Biophys Acta 1813(7):1360–1372. doi:10.1016/j.bbamcr.2010.09.006

    Article  CAS  PubMed  Google Scholar 

  17. Vendelin M, Beraud N, Guerrero K, Andrienko T, Kuznetsov AV, Olivares J, Kay L, Saks VA (2005) Mitochondrial regular arrangement in muscle cells: a “crystal-like” pattern. Am J Physiol Cell Physiol 288(3):C757–C767. doi:10.1152/ajpcell.00281.2004

    Article  CAS  PubMed  Google Scholar 

  18. Anmann T, Eimre M, Kuznetsov AV, Andrienko T, Kaambre T, Sikk P, Seppet E, Tiivel T, Vendelin M, Seppet E, Saks VA (2005) Calcium-induced contraction of sarcomeres changes the regulation of mitochondrial respiration in permeabilized cardiac cells. FEBS J 272(12):3145–3161. doi:10.1111/j.1742-4658.2005.04734.x

    Article  CAS  PubMed  Google Scholar 

  19. Appaix F, Kuznetsov AV, Usson Y, Kay L, Andrienko T, Olivares J, Kaambre T, Sikk P, Margreiter R, Saks V (2003) Possible role of cytoskeleton in intracellular arrangement and regulation of mitochondria. Exp Physiol 88(1):175–190

    Article  CAS  PubMed  Google Scholar 

  20. Kaasik A, Veksler V, Boehm E, Novotova M, Minajeva A, Ventura-Clapier R (2001) Energetic crosstalk between organelles: architectural integration of energy production and utilization. Circ Res 89(2):153–159

    Article  CAS  PubMed  Google Scholar 

  21. Anmann T, Guzun R, Beraud N, Pelloux S, Kuznetsov AV, Kogerman L, Kaambre T, Sikk P, Paju K, Peet N, Seppet E, Ojeda C, Tourneur Y, Saks V (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

    Article  CAS  PubMed  Google Scholar 

  22. Braun U, Paju K, Eimre M, Seppet E, Orlova E, Kadaja L, Trumbeckaite S, Gellerich FN, Zierz S, Jockusch H, Seppet EK (2001) Lack of dystrophin is associated with altered integration of the mitochondria and ATPases in slow-twitch muscle cells of MDX mice. Biochim Biophys Acta 1505(2–3):258–270

    Article  CAS  PubMed  Google Scholar 

  23. Kay L, Li Z, Mericskay M, Olivares J, Tranqui L, Fontaine E, Tiivel T, Sikk P, Kaambre T, Samuel JL, Rappaport L, Usson Y, Leverve X, Paulin D, Saks VA (1997) Study of regulation of mitochondrial respiration in vivo. An analysis of influence of ADP diffusion and possible role of cytoskeleton. Biochim Biophys Acta 1322(1):41–59. doi:10.1016/s0005-2728(97)00071-6

    Article  CAS  PubMed  Google Scholar 

  24. Saks VA, Kaambre T, Sikk P, Eimre M, Orlova E, Paju K, Piirsoo A, Appaix F, Kay L, Regitz-Zagrosek V, Fleck E, Seppet E (2001) Intracellular energetic units in red muscle cells. Biochem J 356(Pt 2):643–657. doi:10.1042/bj3560643

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Winter L, Kuznetsov AV, Grimm M, Zeold A, Fischer I, Wiche G (2015) Plectin isoform P1b and P1d deficiencies differentially affect mitochondrial morphology and function in skeletal muscle. Hum Mol Genet 24(16):4530–4544. doi:10.1093/hmg/ddv184

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Rostovtseva TK, Gurnev PA, Chen MY, Bezrukov SM (2012) Membrane lipid composition regulates tubulin interaction with mitochondrial voltage-dependent anion channel. J Biol Chem 287(35):29589–29598. doi:10.1074/jbc.M112.378778

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Rostovtseva TK, Bezrukov SM (2012) VDAC inhibition by tubulin and its physiological implications. Biochim Biophys Acta 1818(6):1526–1535. doi:10.1016/j.bbamem.2011.11.004

    Article  CAS  PubMed  Google Scholar 

  28. Sheldon KL, Maldonado EN, Lemasters JJ, Rostovtseva TK, Bezrukov SM (2011) Phosphorylation of voltage-dependent anion channel by serine/threonine kinases governs its interaction with tubulin. PLoS ONE 6(10):e25539–e25539. doi:10.1371/journal.pone.0025539

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Maldonado EN, Sheldon KL, DeHart DN, Patnaik J, Manevich Y, Townsend DM, Bezrukov SM, Rostovtseva TK, Lemasters JJ (2013) Voltage-dependent anion channels modulate mitochondrial metabolism in cancer cells: regulation by free tubulin and erastin. J Biol Chem 288(17):11920–11929. doi:10.1074/jbc.M112.433847

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Guzun R, Timohhina N, Tepp K, Monge C, Kaambre T, Sikk P, Kuznetsov AV, Pison C, Saks V (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

    Article  CAS  PubMed  Google Scholar 

  31. Saks V, Kuznetsov AV, Gonzalez-Granillo M, Tepp K, Timohhina N, Karu-Varikmaa M, Kaambre T, Dos Santos P, Boucher F, Guzun R (2012) Intracellular energetic units regulate metabolism in cardiac cells. J Mol Cell Cardiol 52(2):419–436. doi:10.1016/j.yjmcc.2011.07.015

    Article  CAS  PubMed  Google Scholar 

  32. Rostovtseva TK, Bezrukov SM (2008) VDAC regulation: role of cytosolic proteins and mitochondrial lipids. J Bioenerg Biomembr 40(3):163–170. doi:10.1007/s10863-008-9145-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Rostovtseva TK, Sheldon KL, Hassanzadeh E, Monge C, Saks V, Bezrukov SM, Sackett DL (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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Monge C, Beraud N, Tepp K, Pelloux S, Chahboun S, Kaambre T, Kadaja L, Roosimaa M, Piirsoo A, Tourneur Y, Kuznetsov AV, Saks V, Seppet E (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

    Article  CAS  PubMed  Google Scholar 

  35. Anmann T, Varikmaa M, Timohhina N, Tepp K, Shevchuk I, Chekulayev V, Saks V, Kaambre T (2014) Formation of highly organized intracellular structure and energy metabolism in cardiac muscle cells during postnatal development of rat heart. Biochim Biophys Acta 1837(8):1350–1361. doi:10.1016/j.bbabio.2014.03.015

    Article  CAS  PubMed  Google Scholar 

  36. Saks V, Guzun R, Timohhina N, Tepp K, Varikmaa M, Monge C, Beraud N, Kaambre T, Kuznetsov A, Kadaja L, Eimre M, Seppet E (2010) Structure-function relationships in feedback regulation of energy fluxes in vivo in health and disease: mitochondrial interactosome. Biochim Biophys Acta 1797(6–7):678–697. doi:10.1016/j.bbabio.2010.01.011

    Article  CAS  PubMed  Google Scholar 

  37. Kaldma A, Klepinin A, Chekulayev V, Mado K, Shevchuk I, Timohhina N, Tepp K, Kandashvili M, Varikmaa M, Koit A, Planken M, Heck K, Truu L, Planken A, Valvere V, Rebane E, Kaambre T (2014) An in situ study of bioenergetic properties of human colorectal cancer: the regulation of mitochondrial respiration and distribution of flux control among the components of ATP synthasome. Int J Biochem Cell Biol 55:171–186. doi:10.1016/j.biocel.2014.09.004

    Article  CAS  PubMed  Google Scholar 

  38. Puurand U, Kadaja L, Seppet EK (2003) Kindred DNA amplification from two distinct populations of cDNA fragments. Biotechniques 34(5):994–1000

    CAS  PubMed  Google Scholar 

  39. Gonzalez-Granillo M, Grichine A, Guzun R, Usson Y, Tepp K, Chekulayev V, Shevchuk I, Karu-Varikmaa M, Kuznetsov AV, Grimm M, Saks V, Kaambre T (2012) Studies of the role of tubulin beta II isotype in regulation of mitochondrial respiration in intracellular energetic units in cardiac cells. J Mol Cell Cardiol 52(2):437–447. doi:10.1016/j.yjmcc.2011.07.027

    Article  CAS  PubMed  Google Scholar 

  40. Guerrero K, Monge C, Bruckner A, Puurand U, Kadaja L, Kaambre T, Seppet E, Saks V (2010) Study of possible interactions of tubulin, microtubular network, and STOP protein with mitochondria in muscle cells. Mol Cell Biochem 337(1–2):239–249. doi:10.1007/s11010-009-0304-1

    Article  CAS  PubMed  Google Scholar 

  41. Guzun R, Karu-Varikmaa M, Gonzalez-Granillo M, Kuznetsov AV, Michel L, Cottet-Rousselle C, Saaremae M, Kaambre T, Metsis M, Grimm M, Auffray C, Saks V (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

    Article  CAS  PubMed  Google Scholar 

  42. Varikmaa M, Bagur R, Kaambre T, Grichine A, Timohhina N, Tepp K, Shevchuk I, Chekulayev V, Metsis M, Boucher F, Saks V, Kuznetsov AV, Guzun R (2014) Role of mitochondria-cytoskeleton interactions in respiration regulation and mitochondrial organization in striated muscles. Biochim Biophys Acta 1837(2):232–245. doi:10.1016/j.bbabio.2013.10.011

    Article  CAS  PubMed  Google Scholar 

  43. Guzun R, Kaambre T, Bagur R, Grichine A, Usson Y, Varikmaa M, Anmann T, Tepp K, Timohhina N, Shevchuk I, Chekulayev V, Boucher F, Dos Santos P, Schlattner U, Wallimann T, Kuznetsov AV, Dzeja P, Aliev M, Saks V (2015) Modular organization of cardiac energy metabolism: energy conversion, transfer and feedback regulation. Acta Physiol 213(1):84–106. doi:10.1111/apha.12287

    Article  CAS  Google Scholar 

  44. Seppet EK, Kaambre T, Sikk P, Tiivel T, Vija H, Tonkonogi M, Sahlin K, Kay L, Appaix F, Braun U, Eimre M, Saks VA (2001) Functional complexes of mitochondria with Ca, MgATPases of myofibrils and sarcoplasmic reticulum in muscle cells. Biochim Biophys Acta 1504(2–3):379–395 pii]

    Article  CAS  PubMed  Google Scholar 

  45. Saks V, Kuznetsov A, Andrienko T, Usson Y, Appaix F, Guerrero K, Kaambre T, Sikk P, Lemba M, Vendelin M (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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Vendelin M, Eimre M, Seppet E, Peet N, Andrienko T, Lemba M, Engelbrecht J, Seppet EK, Saks VA (2004) Intracellular diffusion of adenosine phosphates is locally restricted in cardiac muscle. Mol Cell Biochem 256–257(1–2):229–241

    Article  PubMed  Google Scholar 

  47. Vendelin M, Eimre M, Seppet E, Peet N, Andrienko T, Lemba M, Engelbrecht J, Seppet EK, Saks VA (2004) Intracellular diffusion of adenosine phosphates is locally restricted in cardiac muscle. Mol Cell Biochem 256(1/2):229–241. doi:10.1023/b:mcbi.0000009871.04141.64

    Article  PubMed  Google Scholar 

  48. Saks VA, Kuznetsov AV, Vendelin M, Guerrero K, Kay L, Seppet EK (2004) Functional coupling as a basic mechanism of feedback regulation of cardiac energy metabolism. Mol Cell Biochem 256–257(1–2):185–199

    Article  PubMed  Google Scholar 

  49. Dzeja PP, Terzic A (2003) Phosphotransfer networks and cellular energetics. J Exp Biol 206(Pt 12):2039–2047

    Article  CAS  PubMed  Google Scholar 

  50. Dzeja PP, Chung S, Terzic A (2007) Integration of adenylate kinase and glycolytic and glycogenolytic circuits in cellular energetics. In: Valdur S (ed) Molecular system bioenergetics. Wiley-VCH, Weinheim, pp 265–301

    Chapter  Google Scholar 

  51. Timohhina N, Guzun R, Tepp K, Monge C, Varikmaa M, Vija H, Sikk P, Kaambre T, Sackett D, Saks V (2009) Direct measurement of energy fluxes from mitochondria into cytoplasm in permeabilized cardiac cells in situ: some evidence for mitochondrial interactosome. J Bioenerg Biomembr 41(3):259–275. doi:10.1007/s10863-009-9224-8

    Article  CAS  PubMed  Google Scholar 

  52. Pedersen PL (2007) Transport ATPases into the year 2008: a brief overview related to types, structures, functions and roles in health and disease. J Bioenerg Biomembr 39(5–6):349–355. doi:10.1007/s10863-007-9123-9

    Article  CAS  PubMed  Google Scholar 

  53. Guzun R, Gonzalez-Granillo M, Karu-Varikmaa M, Grichine A, Usson Y, Kaambre T, Guerrero-Roesch K, Kuznetsov A, Schlattner U, Saks V (2012) Regulation of respiration in muscle cells in vivo by VDAC through interaction with the cytoskeleton and MtCK within mitochondrial interactosome. Biochim Biophys Acta 1818(6):1545–1554. doi:10.1016/j.bbamem.2011.12.034

    Article  CAS  PubMed  Google Scholar 

  54. Tepp K, Shevchuk I, Chekulayev V, Timohhina N, Kuznetsov AV, Guzun R, Saks V, Kaambre T (2011) High efficiency of energy flux controls within mitochondrial interactosome in cardiac intracellular energetic units. Biochim Biophys Acta 1807(12):1549–1561. doi:10.1016/j.bbabio.2011.08.005

    Article  CAS  PubMed  Google Scholar 

  55. Nemutlu E, Gupta A, Zhang S, Viqar M, Holmuhamedov E, Terzic A, Jahangir A, Dzeja P (2015) Decline of phosphotransfer and substrate supply metabolic circuits hinders ATP cycling in aging myocardium. PLoS ONE 10(9):e0136556. doi:10.1371/journal.pone.0136556

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Schuyler GT, Yarbrough LR (1990) Effects of age on myosin and creatine kinase isoforms in left ventricles of Fischer 344 rats. Mech Ageing Dev 56(1):23–38. doi:10.1016/0047-6374(90)90112-s

    Article  CAS  PubMed  Google Scholar 

  57. Bodyak N, Kang PM, Hiromura M, Sulijoadikusumo I, Horikoshi N, Khrapko K, Usheva A (2002) Gene expression profiling of the aging mouse cardiac myocytes. Nucleic Acids Res 30(17):3788–3794

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Davydov VV, Shvets VN (1999) Different changes in the cytosole creatine kinase isoenzymes from heart of adult and old rats during stress. Exp Gerontol 34(7):885–888

    Article  CAS  PubMed  Google Scholar 

  59. Davydov VV, Shvets VN (1999) Differential changes in the properties of mitochondrial isoenzyme creatine kinase from heart of adult and old rats during stress. Exp Gerontol 34(3):375–378

    Article  CAS  PubMed  Google Scholar 

  60. Doran P, O’Connell K, Gannon J, Kavanagh M, Ohlendieck K (2008) Opposite pathobiochemical fate of pyruvate kinase and adenylate kinase in aged rat skeletal muscle as revealed by proteomic DIGE analysis. Proteomics 8(2):364–377. doi:10.1002/pmic.200700475

    Article  CAS  PubMed  Google Scholar 

  61. Ljubicic V, Menzies KJ, Hood DA (2010) Mitochondrial dysfunction is associated with a pro-apoptotic cellular environment in senescent cardiac muscle. Mech Ageing Dev 131(2):79–88. doi:10.1016/j.mad.2009.12.004

    Article  CAS  PubMed  Google Scholar 

  62. Navarro A, Boveris A (2007) The mitochondrial energy transduction system and the aging process. Am J Physiol Cell Physiol 292(2):C670–C686. doi:10.1152/ajpcell.00213.2006

    Article  CAS  PubMed  Google Scholar 

  63. Rasmussen UF, Krustrup P, Kjaer M, Rasmussen HN (2003) Experimental evidence against the mitochondrial theory of aging. A study of isolated human skeletal muscle mitochondria. Exp Gerontol 38(8):877–886

    Article  CAS  PubMed  Google Scholar 

  64. Picard M, Ritchie D, Wright KJ, Romestaing C, Thomas MM, Rowan SL, Taivassalo T, Hepple RT (2010) Mitochondrial functional impairment with aging is exaggerated in isolated mitochondria compared to permeabilized myofibers. Aging Cell 9(6):1032–1046. doi:10.1111/j.1474-9726.2010.00628.x

    Article  CAS  PubMed  Google Scholar 

  65. Picard M, Wright KJ, Ritchie D, Thomas MM, Hepple RT (2012) Mitochondrial function in permeabilized cardiomyocytes is largely preserved in the senescent rat myocardium. PLoS ONE 7(8):e43003–e43003. doi:10.1371/journal.pone.0043003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Seppet EK, Eimre M, Anmann T, Seppet E, Peet N, Kaambre T, Paju K, Piirsoo A, Kuznetsov AV, Vendelin M, Gellerich FN, Zierz S, Saks VA (2005) Intracellular energetic units in healthy and diseased hearts. Exp Clin Cardiol 10(3):173–183

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Stanley WC, Recchia FA, Lopaschuk GD (2005) Myocardial substrate metabolism in the normal and failing heart. Physiol Rev 85(3):1093–1129. doi:10.1152/physrev.00006.2004

    Article  CAS  PubMed  Google Scholar 

  68. Taegtmeyer H, Young ME, Lopaschuk GD, Abel ED, Brunengraber H, Darley-Usmar V, Des Rosiers C, Gerszten R, Glatz JF, Griffin JL, Gropler RJ, Holzhuetter HG, Kizer JR, Lewandowski ED, Malloy CR, Neubauer S, Peterson LR, Portman MA, Recchia FA, Van Eyk JE, Wang TJ, American Heart Association Council on Basic Cardiovascular S (2016) Assessing cardiac metabolism: a scientific statement from the american heart association. Circ Res 118 (10):1659–1701. doi:10.1161/RES.0000000000000097

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Lopaschuk GD, Jaswal JS (2010) Energy metabolic phenotype of the cardiomyocyte during development, differentiation, and postnatal maturation. J Cardiovasc Pharmacol 56(2):130–140. doi:10.1097/FJC.0b013e3181e74a14

    Article  CAS  PubMed  Google Scholar 

  70. Razeghi P, Young ME, Alcorn JL, Moravec CS, Frazier OH, Taegtmeyer H (2001) Metabolic gene expression in fetal and failing human heart. Circulation 104(24):2923–2931

    Article  CAS  PubMed  Google Scholar 

  71. Rajabi M, Kassiotis C, Razeghi P, Taegtmeyer H (2007) Return to the fetal gene program protects the stressed heart: a strong hypothesis. Heart Fail Rev 12(3–4):331–343. doi:10.1007/s10741-007-9034-1

    Article  CAS  PubMed  Google Scholar 

  72. Griffin JL, Atherton H, Shockcor J, Atzori L (2011) Metabolomics as a tool for cardiac research. Nat Rev Cardiol 8(11):630–643. doi:10.1038/nrcardio.2011.138

    Article  CAS  PubMed  Google Scholar 

  73. Heather LC, Wang X, West JA, Griffin JL (2013) A practical guide to metabolomic profiling as a discovery tool for human heart disease. J Mol Cell Cardiol 55:2–11. doi:10.1016/j.yjmcc.2012.12.001

    Article  CAS  PubMed  Google Scholar 

  74. Turer AT (2013) Using metabolomics to assess myocardial metabolism and energetics in heart failure. J Mol Cell Cardiol 55:12–18. doi:10.1016/j.yjmcc.2012.08.025

    Article  CAS  PubMed  Google 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):302–311

    Article  CAS  PubMed  Google Scholar 

  76. 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

    Article  CAS  PubMed  Google Scholar 

  77. Saks VA, Veksler VI, Kuznetsov AV, Kay L, Sikk P, Tiivel T, Tranqui L, Olivares J, Winkler K, Wiedemann F, Kunz WS (1998) Permeabilized cell and skinned fiber techniques in studies of mitochondrial function in vivo. Mol Cell Biochem 184(1–2):81–100

    Article  CAS  PubMed  Google Scholar 

  78. Guzun R, Timohhina N, Tepp K, Gonzalez-Granillo M, Shevchuk I, Chekulayev V, Kuznetsov AV, Kaambre T, Saks VA (2011) Systems bioenergetics of creatine kinase networks: physiological roles of creatine and phosphocreatine in regulation of cardiac cell function. Amino Acids 40(5):1333–1348. doi:10.1007/s00726-011-0854-x

    Article  CAS  PubMed  Google Scholar 

  79. Klepinin A, Ounpuu L, Guzun R, Chekulayev V, Timohhina N, Tepp K, Shevchuk I, Schlattner U, Kaambre T (2016) Simple oxygraphic analysis for the presence of adenylate kinase 1 and 2 in normal and tumor cells. J Bioenerg Biomembr 48(5):531–548. doi:10.1007/s10863-016-9687-3

    Article  CAS  PubMed  Google Scholar 

  80. Robey RB, Raval BJ, Ma J, Santos AV (2000) Thrombin is a novel regulator of hexokinase activity in mesangial cells. Kidney Int 57(6):2308–2318

    Article  CAS  PubMed  Google Scholar 

  81. Neubauer S, Horn M, Cramer M, Harre K, Newell JB, Peters W, Pabst T, Ertl G, Hahn D, Ingwall JS, Kochsiek K (1997) Myocardial phosphocreatine-to-ATP ratio is a predictor of mortality in patients with dilated cardiomyopathy. Circulation 96(7):2190–2196

    Article  CAS  PubMed  Google Scholar 

  82. Gupta A, Akki A, Wang Y, Leppo MK, Chacko VP, Foster DB, Caceres V, Shi S, Kirk JA, Su J, Lai S, Paolocci N, Steenbergen C, Gerstenblith G, Weiss RG (2012) Creatine kinase-mediated improvement of function in failing mouse hearts provides causal evidence the failing heart is energy starved. J Clin Invest 122(1):291–302. doi:10.1172/JCI57426

    Article  CAS  PubMed  Google Scholar 

  83. Esterhammer R, Klug G, Wolf C, Mayr A, Reinstadler S, Feistritzer HJ, Metzler B, Schocke MF (2014) Cardiac high-energy phosphate metabolism alters with age as studied in 196 healthy males with the help of 31-phosphorus 2-dimensional chemical shift imaging. PLoS ONE 9(6):e97368. doi:10.1371/journal.pone.0097368

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  84. Piquereau J, Novotova M, Fortin D, Garnier A, Ventura-Clapier R, Veksler V, Joubert F (2010) Postnatal development of mouse heart: formation of energetic microdomains. J Physiol 588 (Pt 13):2443–2454. doi:10.1113/jphysiol.2010.189670

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Roosimaa M, Podramagi T, Kadaja L, Ruusalepp A, Paju K, Puhke R, Eimre M, Orlova E, Piirsoo A, Peet N, Gellerich FN, Seppet E (2013) Dilation of human atria: increased diffusion restrictions for ADP, overexpression of hexokinase 2 and its coupling to oxidative phosphorylation in cardiomyocytes. Mitochondrion 13(5):399–409. doi:10.1016/j.mito.2012.12.005

    Article  CAS  PubMed  Google Scholar 

  86. Pedersen PL (2007) 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

    Article  CAS  PubMed  Google Scholar 

  87. Mathupala SP, Ko YH, Pedersen PL (2009) Hexokinase-2 bound to mitochondria: cancer’s stygian link to the “Warburg Effect” and a pivotal target for effective therapy. Semin Cancer Biol 19(1):17–24. doi:10.1016/j.semcancer.2008.11.006

    Article  CAS  PubMed  Google Scholar 

  88. Schaffer SW, Jong CJ, Ramila KC, Azuma J (2010) Physiological roles of taurine in heart and muscle. J Biomed Sci 17(Suppl 1):S2–S2. doi:10.1186/1423-0127-17-s1-s2

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  89. Lewis M, Littlejohns B, Lin H, Angelini GD, Suleiman MS (2014) Cardiac taurine and principal amino acids in right and left ventricles of patients with either aortic valve stenosis or coronary artery disease: the importance of diabetes and gender. SpringerPlus 3:523. doi:10.1186/2193-1801-3-523

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  90. Roncalli J, Smih F, Desmoulin F, Dumonteil N, Harmancey R, Hennig S, Perez L, Pathak A, Galinier M, Massabuau P, Malet-Martino M, Senard JM, Rouet P (2007) NMR and cDNA array analysis prior to heart failure reveals an increase of unsaturated lipids, a glutamine/glutamate ratio decrease and a specific transcriptome adaptation in obese rat heart. J Mol Cell Cardiol 42(3):526–539. doi:10.1016/j.yjmcc.2006.11.007

    Article  CAS  PubMed  Google Scholar 

  91. Perrine SA, Michaels MS, Ghoddoussi F, Hyde EM, Tancer ME, Galloway MP (2009) Cardiac effects of MDMA on the metabolic profile determined with 1H-magnetic resonance spectroscopy in the rat. NMR Biomed 22(4):419–425. doi:10.1002/nbm.1352

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Bartelds B, Knoester H, Beaufort-Krol GC, Smid GB, Takens J, Zijlstra WG, Heymans HS, Kuipers JR (1999) Myocardial lactate metabolism in fetal and newborn lambs. Circulation 99(14):1892–1897

    Article  CAS  PubMed  Google Scholar 

  93. Salabei JK, Lorkiewicz PK, Holden CR, Li Q, Hong KU, Bolli R, Bhatnagar A, Hill BG (2015) Glutamine regulates cardiac progenitor cell metabolism and proliferation. Stem Cells 33(8):2613–2627. doi:10.1002/stem.2047

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  94. Tatarkova Z, Kuka S, Racay P, Lehotsky J, Dobrota D, Mistuna D, Kaplan P (2011) Effects of aging on activities of mitochondrial electron transport chain complexes and oxidative damage in rat heart. Physiol Res/Academia Scientiarum Bohemoslovaca 60(2):281–289

    CAS  Google Scholar 

  95. Weber TA, Reichert AS (2010) Impaired quality control of mitochondria: aging from a new perspective. Exp Gerontol 45(7–8):503–511. doi:10.1016/j.exger.2010.03.018

    Article  CAS  PubMed  Google Scholar 

  96. Saks V, Schlattner U, Tokarska-Schlattner M, Wallimann T, Bagur R, Zorman S, Pelosse M, Santos PD, Boucher F, Kaambre T, Guzun R (2014) Systems level regulation of cardiac energy fluxes via metabolic cycles: role of creatine, phosphotransfer pathways, and AMPK signaling. Springer Ser Biophys 16:261–320. doi:10.1007/978-3-642-38505-6_11

    Article  CAS  Google Scholar 

  97. Monge C, Guzun R, Tepp K, Timohhina N, Varikmaa M, Sikk P, Kaambre T, Saks V (2010) Mitochondrial interactosome in health and disease: structural and functional aspects of molecular system bioenergetics of muscle and neuronal cells. In: Svensson OL (ed) Mitochondria: structure, functions and dysfunctions. Cell biology research progress. Nova Science Pub Inc, Hauppauge, pp 441–470

    Google Scholar 

  98. 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):1137–1143

    Article  CAS  PubMed  Google Scholar 

  99. Dzeja PP, Hoyer K, Tian R, Zhang S, Nemutlu E, Spindler M, Ingwall JS (2011) Rearrangement of energetic and substrate utilization networks compensate for chronic myocardial creatine kinase deficiency. J Physiol 589(Pt 21):5193–5211. doi:10.1113/jphysiol.2011.212829

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Nemutlu E, Zhang S, Gupta A, Juranic NO, Macura SI, Terzic A, Jahangir A, Dzeja P (2012) Dynamic phosphometabolomic profiling of human tissues and transgenic models by 18O-assisted (3)(1)P NMR and mass spectrometry. Physiol Genomics 44(7):386–402. doi:10.1152/physiolgenomics.00152.2011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Neubauer S (2007) The failing heart—an engine out of fuel. N Engl J Med 356(11):1140–1151. doi:10.1056/NEJMra063052

    Article  PubMed  Google Scholar 

  102. Nuss JE, Amaning JK, Bailey CE, DeFord JH, Dimayuga VL, Rabek JP, Papaconstantinou J (2009) Oxidative modification and aggregation of creatine kinase from aged mouse skeletal muscle. Aging 1(6):557–572. doi:10.18632/aging.100055

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Goodwin GW, Taylor CS, Taegtmeyer H (1998) Regulation of energy metabolism of the heart during acute increase in heart work. J Biol Chem 273(45):29530–29539. doi:10.1074/jbc.273.45.29530

    Article  CAS  PubMed  Google Scholar 

  104. Venturini A, Ascione R, Lin H, Polesel E, Angelini GD, Suleiman MS (2009) The importance of myocardial amino acids during ischemia and reperfusion in dilated left ventricle of patients with degenerative mitral valve disease. Mol Cell Biochem 330(1–2):63–70. doi:10.1007/s11010-009-0101-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Alkass K, Panula J, Westman M, Wu T-D, Guerquin-Kern J-L, Bergmann O (2015) No evidence for cardiomyocyte number expansion in preadolescent mice. Cell 163(4):1026–1036. doi:10.1016/j.cell.2015.10.035

    Article  CAS  PubMed  Google Scholar 

  106. Dowell RT (1987) Phosphorylcreatine shuttle enzymes during perinatal heart development. Biochem Med Metab Biol 37(3):374–384

    Article  CAS  PubMed  Google Scholar 

  107. Zervou S, Yin X, Nabeebaccus AA, O’Brien BA, Cross RL, McAndrew DJ, Atkinson RA, Eykyn TR, Mayr M, Neubauer S, Lygate CA (2016) Proteomic and metabolomic changes driven by elevating myocardial creatine suggest novel metabolic feedback mechanisms. Amino Acids 48:1–13. doi:10.1007/s00726-016-2236-x

    Article  CAS  Google Scholar 

  108. Muench F, Retel J, Jeuthe S, O H-Ici D, van Rossum B, Wassilew K, Schmerler P, Kuehne T, Berger F, Oschkinat H, Messroghli DR (2015) Alterations in creatine metabolism observed in experimental autoimmune myocarditis using ex vivo proton magic angle spinning MRS. NMR Biomed 28 (12):1625–1633. doi:10.1002/nbm.3415

    Article  CAS  PubMed  Google Scholar 

  109. Marcinkiewicz J, Kontny E (2014) Taurine and inflammatory diseases. Amino Acids 46(1):7–20. doi:10.1007/s00726-012-1361-4

    Article  CAS  PubMed  Google Scholar 

  110. Huxtable RJ (1992) Physiological actions of taurine. Physiol Rev 72(1):101–163

    CAS  PubMed  Google Scholar 

  111. Lotto AA, Ascione R, Caputo M, Bryan AJ, Angelini GD, Suleiman MS (2003) Myocardial protection with intermittent cold blood during aortic valve operation: antegrade versus retrograde delivery. Ann Thorac Surg 76(4):1227–1233; discussion 1233

    Article  PubMed  Google Scholar 

  112. Modi P, Suleiman MS (2004) Myocardial taurine, development and vulnerability to ischemia. Amino Acids 26(1):65–70. doi:10.1007/s00726-003-0031-y

    Article  CAS  PubMed  Google Scholar 

  113. Bak MI, Wei JY, Ingwall JS (1998) Interaction of hypoxia and aging in the heart: analysis of high energy phosphate content. J Mol Cell Cardiol 30(3):661–672. doi:10.1006/jmcc.1997.0633

    Article  CAS  PubMed  Google Scholar 

  114. Hollingsworth KG, Blamire AM, Keavney BD, Macgowan GA (2012) Left ventricular torsion, energetics, and diastolic function in normal human aging. Am J Physiol Heart Circ Physiol 302(4):H885–H892. doi:10.1152/ajpheart.00985.2011

    Article  CAS  PubMed  Google Scholar 

  115. Griffin JL, Williams HJ, Sang E, Clarke K, Rae C, Nicholson JK (2001) Metabolic profiling of genetic disorders: a multitissue (1)H nuclear magnetic resonance spectroscopic and pattern recognition study into dystrophic tissue. Anal Biochem 293(1):16–21. doi:10.1006/abio.2001.5096

    Article  CAS  PubMed  Google Scholar 

  116. Goodpaster BH, Park SW, Harris TB, Kritchevsky SB, Nevitt M, Schwartz AV, Simonsick EM, Tylavsky FA, Visser M, Newman AB (2006) The loss of skeletal muscle strength, mass, and quality in older adults: the health, aging and body composition study. J Gerontol A 61(10):1059–1064

    Article  Google Scholar 

  117. Mellor KM, Curl CL, Chandramouli C, Pedrazzini T, Wendt IR, Delbridge LM (2014) Ageing-related cardiomyocyte functional decline is sex and angiotensin II dependent. Age 36(3):9630. doi:10.1007/s11357-014-9630-7

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  118. Howlett SE (2010) Age-associated changes in excitation-contraction coupling are more prominent in ventricular myocytes from male rats than in myocytes from female rats. Am J Physiol Heart Circ Physiol 298(2):H659–H670. doi:10.1152/ajpheart.00214.2009

    Article  CAS  PubMed  Google Scholar 

  119. Callahan DM, Bedrin NG, Subramanian M, Berking J, Ades PA, Toth MJ, Miller MS (2014) Age-related structural alterations in human skeletal muscle fibers and mitochondria are sex specific: relationship to single-fiber function. J Appl Physiol 116(12):1582–1592. doi:10.1152/japplphysiol.01362.2013

    Article  PubMed  PubMed Central  Google Scholar 

  120. Miller MS, Bedrin NG, Callahan DM, Previs MJ, Jennings ME 2nd, Ades PA, Maughan DW, Palmer BM, Toth MJ (2013) Age-related slowing of myosin actin cross-bridge kinetics is sex specific and predicts decrements in whole skeletal muscle performance in humans. J Appl Physiol 115(7):1004–1014. doi:10.1152/japplphysiol.00563.2013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

Research sponsored by the institutional research funding IUT23-1 and IUT23-7 of the Estonian Ministry of Education and Research and the European Regional Development Fund project TK134. The skillful technical assistance by Aivar Uus and Marko Rõõmusoks is gratefully acknowledged.

Author information

Authors and Affiliations

  1. Laboratory of Bioenergetics, National Institute of Chemical Physics and Biophysics, Akadeemia tee 23, 12618, Tallinn, Estonia

    Kersti Tepp, Marju Puurand, Natalja Timohhina, Aleksandr Klepinin, Laura Truu, Igor Shevchuk, Vladimir Chekulayev & Tuuli Kaambre

  2. Laboratory of Chemical Physics, National Institute of Chemical Physics and Biophysics, Tallinn, Estonia

    Jasper Adamson

  3. School of Natural Sciences and Health, Tallinn University, Tallinn, Estonia

    Tuuli Kaambre

Authors
  1. Kersti Tepp
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marju Puurand
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Natalja Timohhina
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jasper Adamson
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Aleksandr Klepinin
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Laura Truu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Igor Shevchuk
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Vladimir Chekulayev
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Tuuli Kaambre
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kersti Tepp.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All applicable international, national, and institutional guidelines for the care and use of animals were followed. The animals were studied in accordance to the “Guide for the Care and Use of the Laboratory Animals” published by the US National Institute of Health (NIH publication no. 85-23, revised 1996). Animal procedures were approved by the Estonian National Committee for Ethics in Animal Experimentation (Estonian Ministry of Agriculture).

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 173 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tepp, K., Puurand, M., Timohhina, N. et al. Changes in the mitochondrial function and in the efficiency of energy transfer pathways during cardiomyocyte aging. Mol Cell Biochem 432, 141–158 (2017). https://doi.org/10.1007/s11010-017-3005-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-017-3005-1

Keywords

Search

Navigation