Journal of Molecular Medicine

, Volume 82, Issue 9, pp 565–578 | Cite as

Heart mitochondria signaling pathways: appraisal of an emerging field

  • José Marín-GarcíaEmail author
  • Michael J. Goldenthal


The contribution that mitochondria make to cardiac function extends well beyond their critical bioenergetic role as a supplier of ATP. The organelle plays an integral part in the regulatory and signaling events that occur in response to physiological stresses, including but not limited to myocardial ischemia and reperfusion, hypoxia, oxidative stress, and hormonal and cytokine stimuli. Research on both intact cardiac muscle tissue and cultured cardiomyocytes has just begun to probe the nature and the extent of mitochondrial involvement in interorganelle communication, hypertropic growth, and cell death. This review covers particular aspects of the newly emerging field of mitochondrial medicine offering a critical guide in the assessment of mitochondrial participation at the molecular and biochemical levels in the multiple and interrelated signaling pathways, gauging the effect that mitochondria have as a receiver, integrator, and transmitter of signals on cardiac phenotype. We also discuss future directions that may impact on the treatment of cardiac diseases.


Cardioprotection Mitochondria Signal transduction 



Adenine nucleotide translocator


Coenzyme A


Cytochrome c oxidase


Endoplasmic reticulum


Electron transport chain


Fatty acid oxidation


Hypertropic cardiomyopathy


Insulin-like growth factor


Mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes


Myoclonic epilepsy and ragged-red fibers


Mitochondrial ATP-sensitive potassium


Mammalian target of rapamycin


Mitochondrial transcription factor


Nuclear factor κ beta


Nuclear respiratory factor


Oxidative phosphorylation


Phosphatidylinositol 3-kinase


Protein kinase A


Protein kinase C


Peroxisome proliferator activated receptor


Permeability transition


Reactive oxygen species


Superoxide dismutase


Tricarboxylic acid


Thyroid hormone


Uncoupling protein


  1. 1.
    Marin-Garcia J, Goldenthal MJ (2002) Understanding the impact of mitochondrial defects in cardiovascular disease: a review. J Card Fail 8:347–361CrossRefPubMedGoogle Scholar
  2. 2.
    Marin-Garcia J, Ananthakrishnan R, Goldenthal MJ, Pierpont ME (2000) Biochemical and molecular basis for mitochondrial cardiomyopathy in neonates and children. J Inherit Metab Dis 23:625–633CrossRefGoogle Scholar
  3. 3.
    Lewis W, Dalakas MC (1995) Mitochondrial toxicity of antiviral drugs. Nat Med1:417–422Google Scholar
  4. 4.
    Benit P, Slama A, Cartault F, Giurgea I, Chretien D, Lebon S, Marsac C, Munnich A, Rotig A, Rustin P (2004) Mutant NDUFS3 subunit of mitochondrial complex I causes Leigh syndrome. J Med Genet 41:14–17CrossRefPubMedGoogle Scholar
  5. 5.
    Papadopoulou LC, Sue CM, Davidson MM, Tanji K, Nishino I, Sadlock JE, Krishna S, Walker W, Selby J, Glerum DM, Coster RV, Lyon G, Scalais E, Lebel R, Kaplan P, Shanske S, De Vivo DC, Bonilla E, Hirano M, DiMauro S, Schon EA (1999) Fatal infantile cardioencephalomyopathy with COX deficiency and mutations in SCO2, a COX assembly gene. Nat Genet 23:333–337PubMedGoogle Scholar
  6. 6.
    Lodi R, Cooper JM, Bradley JL, Manners D, Styles P, Taylor DJ, Schapira AH (1999) Deficit of in vivo mitochondrial ATP production in patients with Friedreich ataxia. Proc Natl Acad Sci U S A 96:11492–11495CrossRefPubMedGoogle Scholar
  7. 7.
    Zeviani M, Spinazzola A, Carelli V (2003) Nuclear genes in mitochondrial disorders. Curr Opin Genet Dev 13:262–270CrossRefPubMedGoogle Scholar
  8. 8.
    Graham BH, Waymire KG, Cottrell B, Trounce IA, MacGregor GR, Wallace DC (1997) A mouse model for mitochondrial myopathy and cardiomyopathy resulting from a deficiency in the heart/muscle isoform of the adenine nucleotide translocator. Nat Genet 16:226–234PubMedGoogle Scholar
  9. 9.
    Lebovitz RM, Zhang H, Vogel H, Cartwright J Jr, Dionne L, Lu N, Huang S, Matzuk MM (1996) Neurodegeneration, myocardial injury, and perinatal death in mitochondrial superoxide dismutase-deficient mice. Proc Natl Acad Sci USA 93:9782–9787CrossRefPubMedGoogle Scholar
  10. 10.
    Puccio H, Simon D, Cossee M, Criqui-Filipe P, Tiziano F, Melki J, Hindelang C, Matyas R, Rustin P, Koenig M (2001) Mouse models for Friedreich ataxia exhibit cardiomyopathy, sensory nerve defect and Fe-S enzyme deficiency followed by intramitochondrial iron deposits. Nat Genet 27:181–186CrossRefPubMedGoogle Scholar
  11. 11.
    Wang J, Wilhelmsson H, Graff C, Li H, Oldfors A, Rustin P, Bruning JC, Kahn CR, Clayton DA, Barsh GS, Thoren P, Larsson NG (1999) Dilated cardiomyopathy and atrioventricular conduction blocks induced by heart-specific inactivation of mtDNA gene expression. Nat Genet 21:133–137CrossRefPubMedGoogle Scholar
  12. 12.
    Corbucci GG (2000) Adaptive changes in response to acute hypoxia, ischemia and reperfusion in human cardiac cell. Minerva Anestesiol 66:523–530PubMedGoogle Scholar
  13. 13.
    Ylitalo K, Ala-Rami A, Vuorinen K, Peuhkurinen K, Lepojarvi M, Kaukoranta P, Kiviluoma K, Hassinen I (2001) Reversible ischemic inhibition of F(1) F(0)-ATPase in rat and human myocardium. Biochim Biophys Acta 1504:329–339CrossRefPubMedGoogle Scholar
  14. 14.
    Corral-Debrinski M, Stepien G, Shoffner JM, Lott MT, Kanter K, Wallace DC (1991) Hypoxemia is associated with mitochondrial DNA damage and gene induction. Implications for cardiac disease. JAMA 266:1812–1816CrossRefPubMedGoogle Scholar
  15. 15.
    Regula KM, Ens K, Kirshenbaum LA (2003) Mitochondria-assisted suicide: a license to kill. J Mol Cell Cardiol 35:559–567CrossRefPubMedGoogle Scholar
  16. 16.
    Gottleib RA, Burleson KO, Kloner RA, Babior BM, Engler RL (1994) Reperfusion injury induces apoptosis in rabbit cardiomyocytes. J Clin Invest 94:1621–1628PubMedGoogle Scholar
  17. 17.
    Paradies G, Petrosillo G, Pistolese M, Di Venosa N, Serena D, Ruggiero FM (1999) Lipid peroxidation and alterations to oxidative metabolism in mitochondria isolated from rat heart subjected to ischemia and reperfusion. Free Radic Biol Med 27:42–50CrossRefPubMedGoogle Scholar
  18. 18.
    Schulz R, Cohen MV, Behrends M, Downey JM, Heusch G (2001) Signal transduction of ischemic preconditioning. Cardiovasc Res 52:181–198PubMedGoogle Scholar
  19. 19.
    Marin-Garcia J, Goldenthal MJ (2004) Mitochondria play a critical role in cardioprotection. J Card Fail 10:55–66CrossRefPubMedGoogle Scholar
  20. 20.
    O’Rourke B (2000) Myocardial KATP channels in preconditioning. Circ Res 87:845–855PubMedGoogle Scholar
  21. 21.
    Cohen MV, Baines CP, Downey JM (2000) Ischemic preconditioning: from adenosine receptor of KATP channel. Annu Rev Physiol 62:79–109PubMedGoogle Scholar
  22. 22.
    Das M, Parker JE, Halestrap AP (2003) Matrix volume measurements challenge the existence of diazoxide/glibencamide-sensitive KATP channels in rat mitochondria. J Physiol (Lond) 547:893–902Google Scholar
  23. 23.
    Halestrap AP (1994) Regulation of mitochondrial metabolism through changes in matrix volume. Biochem Soc Trans 22:522–529PubMedGoogle Scholar
  24. 24.
    Garlid KD, Paucek P, Yarov-Yarovoy V, Murray HN, Darbenzio R, D’Alonzo AJ, Lodge NJ, Smith MA, Grover GJ (1997) Cardioprotective effect of diazoxide and its interaction with mitochondrial ATP-sensitive K+ channels. Possible mechanism of cardioprotection. Circ Res 81:1072–1082PubMedGoogle Scholar
  25. 25.
    Akao M, Teshima Y, Marban E (2002) Antiapoptotic effect of nicorandil mediated by mitochondrial atp-sensitive potassium channels in cultured cardiac myocytes. J Am Coll Cardiol 40:803–810CrossRefPubMedGoogle Scholar
  26. 26.
    Ning XH, Xu CS, Song YC, Xiao Y, Hu YJ, Lupinetti FM, Portman MA (1998) Hypothermia preserves function and signaling for mitochondrial biogenesis during subsequent ischemia. Am J Physiol 274:H786–H793PubMedGoogle Scholar
  27. 27.
    Nadal-Ginard B, Kajstura J, Leri A, Anversa P (2003) Myocyte death, growth, and regeneration in cardiac hypertrophy and failure. Circ Res 92:139–150PubMedGoogle Scholar
  28. 28.
    Colucci WS (1997) Molecular and cellular mechanisms of myocardial failure. Am J Cardiol 80:15L–25LPubMedGoogle Scholar
  29. 29.
    Hunter JJ, Chien KR (1999) Signaling pathways for cardiac hypertrophy and failure. N Engl J Med 341:1276–1283PubMedGoogle Scholar
  30. 30.
    Katz AM (2002) Maladaptive growth in the failing heart: the cardiomyopathy of overload. Cardiovasc Drugs Ther 16:245–249CrossRefPubMedGoogle Scholar
  31. 31.
    Kang PM, Yue P, Liu Z, Tarnavski O, Bodyak N, Izumo S (2004) Alterations in apoptosis regulatory factors during hypertrophy and heart failure. Am J Physiol Heart Circ Physiol 4 March 4 (epub ahead of print)Google Scholar
  32. 32.
    Sack MN, Kelly DP (1998) The energy substrate switch during development of heart failure; gene regulatory mechanisms. Int J Mol Med 1:17–24PubMedGoogle Scholar
  33. 33.
    Lehman JJ, Kelly DP (2002) Gene regulatory mechanisms governing energy metabolism during cardiac hypertrophic growth. Heart Fail Rev 7:175–185CrossRefPubMedGoogle Scholar
  34. 34.
    Zak R, Rabinowitz M, Rajamanickam C, Merten S, Kwiatkowska-Patzer B (1980) Mitochondrial proliferation in cardiac hypertrophy. Basic Res Cardiol 75:171–178PubMedGoogle Scholar
  35. 35.
    Lucas DT, Aryal P, Szweda LI, Koch WJ, Leinwand LA (2003) Alterations in mitochondrial function in a mouse model of hypertrophic cardiomyopathy. Am J Physiol Heart Circ Physiol 284:H575–H583PubMedGoogle Scholar
  36. 36.
    Marin-Garcia J, Goldenthal MJ, Moe GW (2001) Mitochondrial pathology in cardiac failure. Cardiovasc Res 49:17–26CrossRefPubMedGoogle Scholar
  37. 37.
    Blair E, Redwood C, Ashrafian H, Oliveira M, Broxholme J, Kerr B, Salmon A, Ostman-Smith I, Watkins H (2001) Mutations in the gamma (2) subunit of AMP-activated protein kinase cause familial hypertrophic cardiomyopathy: evidence for the central role of energy compromise in disease pathogenesis. Hum Mol Genet 10:1215–1220PubMedGoogle Scholar
  38. 38.
    Tardiff JC, Hewett TE, Palmer BM, Olsson C, Factor SM, Moore RL, Robbins J, Leinwand LA (1999) Cardiac troponin T mutations result in allele-specific phenotypes in a mouse model for hypertrophic cardiomyopathy. J Clin Invest 104:469–481PubMedGoogle Scholar
  39. 39.
    Fananapazir L, Dalakas MC, Cyran F, Cohn G, Epstein ND (1993) Missense mutations in the beta-myosin heavy-chain gene cause central core disease in hypertrophic cardiomyopathy. Proc Natl Acad Sci USA 90:3993–3997PubMedGoogle Scholar
  40. 40.
    Sayen MR, Gustafsson AB, Sussman MA, Molkentin JD, Gottlieb RA (2003) Calcineurin transgenic mice have mitochondrial dysfunction and elevated superoxide production. Am J Physiol Cell Physiol 284:C562–C570PubMedGoogle Scholar
  41. 41.
    Scarpulla RC (2002) Nuclear activators and coactivators in mammalian mitochondrial biogenesis. Biochim Biophys Acta 1576:1–14CrossRefPubMedGoogle Scholar
  42. 42.
    Goffart S, Wiesner RJ (2003) Regulation and co-ordination of nuclear gene expression during mitochondrial biogenesis. Exp Physiol 88:33–40CrossRefPubMedGoogle Scholar
  43. 43.
    Xia Y, Buja LM, Scarpulla RC, McMillin JB (1997) Electrical stimulation of neonatal cardio-myocytes results in sequential activation of nuclear genes governing mitochondrial proliferation and differentiation. Proc Natl Acad Sci USA 94:11399–11404CrossRefPubMedGoogle Scholar
  44. 44.
    Lehman JJ, Barger PM, Kovacs A, Saffitz JE, Medeiros DM, Kelly DP (2000) Peroxisome proliferator-activated receptor gamma coactivator-1 promotes cardiac mitochondrial biogenesis. J Clin Invest 106:847–856PubMedGoogle Scholar
  45. 45.
    Gilde AJ, van der Lee KA, Willemsen PH, Chinetti G, van der Leij FR, van der Vusse GJ, Staels B, van Bilsen M (2003) Peroxisome proliferator-activated receptor PPARalpha and PPARbeta/delta, but not PPARgamma, modulate the expression of genes involved in cardiac lipid metabolism. Circ Res 92:518–524CrossRefPubMedGoogle Scholar
  46. 46.
    Barger PM, Kelly DP (2000) PPAR signaling in the control of cardiac energy metabolism. Trends Cardiovasc Med 10:238–245CrossRefPubMedGoogle Scholar
  47. 47.
    Djouadi F, Brandt JM, Weinheimer CJ, Leone TC, Gonzalez FJ, Kelly DP (1999) The role of the peroxisome proliferator-activated receptor alpha (PPAR α) in the control of cardiac lipid metabolism. Prostaglandins Leukot Essent Fatty Acids 60:339–343CrossRefPubMedGoogle Scholar
  48. 48.
    Garnier A, Fortin D, Delomenie C, Momken I, Veksler V, Ventura-Clapier R (2003) Depressed mitochondrial transcription factors and oxidative capacity in rat failing cardiac and skeletal muscles. J Physiol (Lond) 551:491–501Google Scholar
  49. 49.
    Huss JM, Levy FH, Kelly DP (2001) Hypoxia inhibits the peroxisome proliferator-activated receptor alpha/retinoid X receptor gene regulatory pathway in cardiac myocytes: a mechanism for O2-dependent modulation of mitochondrial fatty acid oxidation. J Biol Chem 276:27605–27612CrossRefPubMedGoogle Scholar
  50. 50.
    Wu H, Kanatous SB, Thurmond FA, Gallardo T, Isotani E, Bassel-Duby R, Williams RS (2002) Regulation of mitochondrial biogenesis in skeletal muscle by CaMK. Science 296:349–352CrossRefPubMedGoogle Scholar
  51. 51.
    Sack MN, Harrington LS, Jonassen AK, Mjos OD, Yellon DM (2000) Coordinate regulation of metabolic enzyme encoding genes during cardiac development and following carvedilol therapy in spontaneously hypertensive rats. Cardiovasc Drugs Ther 14:31–39CrossRefPubMedGoogle Scholar
  52. 52.
    Bushdid PB, Osinska H, Waclaw RR, Molkentin JD, Yutzey KE (2003) NFATc3 and NFATc4 are required for cardiac development and mitochondrial function. Circ Res 92:1305–1313CrossRefPubMedGoogle Scholar
  53. 53.
    Finck BN, Lehman JJ, Leone TC, Welch MJ, Bennett MJ, Kovacs A, Han X, Gross RW, Kozak R, Lopaschuk GD, Kelly DP (2002) The cardiac phenotype induced by PPARalpha overexpression mimics that caused by diabetes mellitus. J Clin Invest 109:121–130CrossRefPubMedGoogle Scholar
  54. 54.
    Thomson M (2002) Evidence of undiscovered cell regulatory mechanisms: phospho-proteins and protein kinases in mitochondria. Cell Mol Life Sci 59:213–219CrossRefGoogle Scholar
  55. 55.
    Orfali KA, Fryer LG, Holness MJ, Sugden MC (1993) Long-term regulation of pyruvate dehydrogenase kinase by high-fat feeding. Experiments in vivo and in cultured cardiomyocytes. FEBS Lett 336:501–505CrossRefPubMedGoogle Scholar
  56. 56.
    Doering CB, Danner DJ (2000) Amino acid deprivation induces translation of branched-chain α-ketoacid dehydrogenase kinase. Am J Physiol Cell Physiol 279:C1587–C1594PubMedGoogle Scholar
  57. 57.
    Technikova-Dobrova Z, Sardanelli AM, Stanca MR, Papa S (1994) cAMP-dependent protein phosphorylation in mitochondria of bovine heart. FEBS Lett 350:187–191CrossRefPubMedGoogle Scholar
  58. 58.
    Wang Y, Hirai K, Ashraf M (1999) Activation of mitochondrial ATP-sensitive K (+) channel for cardiac protection against ischemic injury is dependent on protein kinase C activity. Circ Res 85:731–741PubMedGoogle Scholar
  59. 59.
    Baines CP, Zhang J, Wang GW, Zheng YT, Xiu JX, Cardwell EM, Bolli R, Ping P (2002) Mitochondrial PKCepsilon and MAPK form signaling modules in the murine heart: enhanced mitochondrial PKCepsilon-MAPK interactions and differential MAPK activation in PKCepsilon-induced cardioprotection. Circ Res 90:390–397CrossRefPubMedGoogle Scholar
  60. 60.
    He H, Li HL, Lin A, Gottlieb RA (1999) Activation of the JNK pathway is important for cardiomyocyte death in response to simulated ischemia. Cell Death Differ 6:987–991CrossRefPubMedGoogle Scholar
  61. 61.
    Baines CP, Song CX, Zheng YT, Wang GW, Zhang J, Wang OL, Guo Y, Bolli R, Cardwell EM, Ping P (2003) Protein kinase Cepsilon interacts with and inhibits the permeability transition pore in cardiac mitochondria. Circ Res 92:873–880CrossRefPubMedGoogle Scholar
  62. 62.
    Fryer RM, Schultz JE, Hsu AK, Gross GJ (1999) Importance of PKC and tyrosine kinase in single or multiple cycles of preconditioning in rat hearts. Am J Physiol Heart Circ Physiol 276:H1229–H1235Google Scholar
  63. 63.
    Chen L, Hahn H, Wu G, Chen CH, Liron T, Schechtman D, Cavallaro G, Banci L, Guo Y, Bolli R, Dorn GW, Mochly-Rosen D (2001) Opposing cardioprotective actions and parallel hypertrophic effects of delta PKC and epsilon PKC. Proc Natl Acad Sci USA 98:11114–11119CrossRefPubMedGoogle Scholar
  64. 64.
    Sardanelli AM, Technikova-Dobrova Z, Scacco SC, Speranza F, Papa S (1995) Characterization of proteins phosphorylated by the cAMP-dependent protein kinase of bovine heart mitochondria. FEBS Lett 377:470–474CrossRefPubMedGoogle Scholar
  65. 65.
    Papa S (2002) The NDUFS4 nuclear gene of complex I of mitochondria and the cAMP cascade. Biochim Biophys Acta 1555:147–1453CrossRefPubMedGoogle Scholar
  66. 66.
    Lee I, Bender E, Kadenbach B (2002) Control of mitochondrial membrane potential and ROS formation by reversible phosphorylation of cytochrome c oxidase. Mol Cell Biochem 234–235:63–70Google Scholar
  67. 67.
    Schulenberg B, Aggeler R, Beechem JM, Capaldi RA, Patton WF (2003) Analysis of steady-state protein phosphorylation in mitochondria using a novel fluorescent phosphosensor dye. J Biol Chem 278:27251–27225PubMedGoogle Scholar
  68. 68.
    He H, Chen M, Scheffler NK, Gibson BW, Spremulli LL, Gottlieb RA (2001) Phosphorylation of mitochondrial elongation factor Tu in ischemic myocardium: basis for chloramphenicol-mediated cardioprotection. Circ Res 89:461–467PubMedGoogle Scholar
  69. 69.
    Rutter GA, Rizzuto R (2000) Regulation of mitochondrial metabolism by ER Ca++ release: an intimate connection. Trends Biochem Sci 25:215–222PubMedGoogle Scholar
  70. 70.
    Duchen M (1999) Contributions of mitochondria to animal physiology: from homeostatic sensor to calcium signalling and cell death. J Physiol (Lond) 516:1–17Google Scholar
  71. 71.
    Griffiths EJ (2000) Use of ruthenium red as an inhibitor of mitochondrial Ca (2+) uptake in single rat cardiomyocytes. FEBS Lett 486:257–260CrossRefPubMedGoogle Scholar
  72. 72.
    Pacher P, Hajnoczky G (2001) Propagation of the apoptotic signal by mitochondrial waves. EMBO J 20:4107–4121CrossRefPubMedGoogle Scholar
  73. 73.
    McCormack JG, Halestrap AP, Denton RM (1990) Role of calcium ions in regulation of mammalian intramitochondrial metabolism. Physiol Rev 70:391–425PubMedGoogle Scholar
  74. 74.
    Robb-Gaspers LD, Burnett P, Rutter GA, Denton RM, Rizzuto R, Thomas AP (1998) Integrating cytosolic calcium signals into mitochondrial metabolic responses. EMBO J 17:4987–5000CrossRefPubMedGoogle Scholar
  75. 75.
    Cortassa S, Aon MA, Marban E, Winslow RL, O’Rourke B (2003) An integrated model of cardiac mitochondrial energy metabolism and calcium dynamics. Biophys J 84:2734–2755PubMedGoogle Scholar
  76. 76.
    Das AM, Harris DA (1991) Control of mitochondrial ATP synthase in rat cardiomyocytes: effects of thyroid hormone. Biochim Biophys Acta 1096:284–290CrossRefPubMedGoogle Scholar
  77. 77.
    Territo PR, Mootha VK, French SA, Balaban RS (2000) Ca(2+) activation of heart mitochondrial oxidative phosphorylation: role of the F(0)/F(1)-ATPase. Am J Physiol Cell Physiol 278:C423–C435PubMedGoogle Scholar
  78. 78.
    Rizzuto R (1998) Close contacts with the endoplasmic reticulum as determinants of mitochondrial Ca++ responses. Science 280:1763–1766PubMedGoogle Scholar
  79. 79.
    Csordas G, Thomas AP, Hajnoczky G (2001) Calcium signal transmission between ryanodine receptors and mitochondria in cardiac muscle. Trends Cardiovasc Med 11:269–275CrossRefPubMedGoogle Scholar
  80. 80.
    Gunter TE, Gunter KK (2001) Uptake of calcium by mitochondria: transport and possible function. IUBMB Life 52:197–204CrossRefPubMedGoogle Scholar
  81. 81.
    Buntinas L, Gunter KK, Sparagna GC, Gunter TE (2001) The rapid mode of calcium uptake into heart mitochondria (RaM): comparison to RaM in liver mitochondria. Biochim Biophys Acta 1504:248–261CrossRefPubMedGoogle Scholar
  82. 82.
    Crompton M, Costi A, Hayat L (1987) Evidence for the presence of a reversible Ca2+-dependent pore activated by oxidative stress in heart mitochondria. Biochem J 245:915–918PubMedGoogle Scholar
  83. 83.
    Hajnoczky G, Csordas G, Yi M (2002) Old players in a new role: mitochondria-associated membranes, VDAC, and ryanodine receptors as contributors to calcium signal propagation from endoplasmic reticulum to the mitochondria. Cell Calcium 32:363–377CrossRefPubMedGoogle Scholar
  84. 84.
    Rapizzi E, Pinton P, Szabadkai G, Wieckowski MR, Vandecasteele G, Baird G, Tuft RA, Fogarty KE, Rizzuto R (2002) Recombinant expression of the voltage dependent anion channel enhances the transfer of Ca2+ microdomains to mitochondria. J Cell Biol 159:613–624Google Scholar
  85. 85.
    Casas F, Rochard P, Rodier A, Cassar-Malek I, Marchal-Victorion S, Wiesner RJ, Cabello G, Wrutniak C (1999) A variant form of the nuclear triiodothyronine receptor c-ErbAalpha1 plays a direct role in regulation of mitochondrial RNA synthesis. Mol Cell Biol 19:7913–7924PubMedGoogle Scholar
  86. 86.
    Scheller K, Seibel P, Sekeris CE (2003) Glucocorticoid and thyroid hormone receptors in mitochondria of animal cells. Int Rev Cytol 222:1–61CrossRefPubMedGoogle Scholar
  87. 87.
    Colavecchia M, Christie LN, Kanwar YS, Hood DA (2003) Functional consequences of thyroid hormone-induced changes in the mitochondrial protein import pathway. Am J Physiol Endocrinol Metab 284:E29–E35PubMedGoogle Scholar
  88. 88.
    Schneider JJ, Hood DA (2000) Effect of thyroid hormone on mtHsp70 expression, mitochondrial import and processing in cardiac muscle. J Endocrinol 165:9–17PubMedGoogle Scholar
  89. 89.
    Oddis CV, Finkel MS (1995) Cytokine-stimulated nitric oxide production inhibits mitochondrial activity in cardiac myocytes. Biochem Biophys Res Commun 213:1002–1009CrossRefPubMedGoogle Scholar
  90. 90.
    Zell R, Geck P, Werdan K, Boekstegers P (1997) TNF-alpha and IL-1 alpha inhibit both pyruvate dehydrogenase activity and mitochondrial function in cardiomyocytes: evidence for primary impairment of mitochondrial function. Mol Cell Biochem 177:61–67CrossRefPubMedGoogle Scholar
  91. 91.
    Sammut IA, Harrison JC (2003) Cardiac mitochondrial complex activity is enhanced by heat shock proteins. Clin Exp Pharmacol Physiol 30:110–115CrossRefPubMedGoogle Scholar
  92. 92.
    Bialik S, Cryns VL, Drincic A, Miyata S, Wollowick AL, Srinivasan A, Kitsis RN (1999) The mitochondrial apoptotic pathway is activated by serum and glucose deprivation in cardiac myocytes. Circ Res 85:403–414PubMedGoogle Scholar
  93. 93.
    Sparagna GC, Hickson-Bick DL, Buja LM, McMillin JB (2001) Fatty acid-induced apoptosis in neonatal cardiomyocytes: redox signaling. Antioxid Redox Signal 3:71–79CrossRefPubMedGoogle Scholar
  94. 94.
    Gudz TI, Tserng KY, Hoppel CL (1997) Direct inhibition of mitochondrial respiratory chain complex III by cell-permeable ceramide. J Biol Chem 272:24154–24158CrossRefPubMedGoogle Scholar
  95. 95.
    Riobo NA, Clementi E, Melani M, Boveris A, Cadenas E, Moncada S, Poderoso JJ (2001) Nitric oxide inhibits mitochondrial NADH: ubiquinone reductase activity through peroxynitrite formation. Biochem J 359:139–145CrossRefPubMedGoogle Scholar
  96. 96.
    Poderoso JJ, Peralta JG, Lisdero CL, Carreras MC, Radisic M, Schopfer F, Cadenas E, Boveris A (1998) Nitric oxide regulates oxygen uptake and hydrogen peroxide release by the isolated beating rat heart. Am J Physiol 274:C112–C119PubMedGoogle Scholar
  97. 97.
    Wiesner RJ, Hornung TV, Garman JD, Clayton DA, O’Gorman E, Wallimann T (1999) Stimulation of mitochondrial gene expression and proliferation of mitochondria following impairment of cellular energy transfer by inhibition of phosphocreatine circuit in rat hearts. J Bioenerg Biomembr 31:559–567CrossRefPubMedGoogle Scholar
  98. 98.
    Tanaka T, Morita H, Koide H, Kawamura K, Takatsu T (1985) Biochemical and morphological study of cardiac hypertrophy. Effects of thyroxine on enzyme activities in the rat myocardium. Basic Res Cardiol 80:165–174Google Scholar
  99. 99.
    Kennedy SG, Kandel ES, Cross TK, Hay N (1999) Akt/protein kinase B inhibits cell death by preventing release of cytochrome c from mitochondria. Mol Cell Biol 19:5800–5810PubMedGoogle Scholar
  100. 100.
    Shioi T, McMullen JR, Kang PM, Douglas PS, Obata T, Franke TF, Cantley LC, Izumo S (2002) Akt/protein kinase B promotes organ growth in transgenic mice. Mol Cell Biol 22:2799–2809CrossRefPubMedGoogle Scholar
  101. 101.
    Condorelli G, Drusco A, Stassi G, Bellacosa A, Roncarati R, Iaccarino G, Russo MA, Gu Y, Dalton N, Chung C, Latronico MV, Napoli C, Sadoshima J, Croce CM, Ross J (2002) Akt induces enhanced myocardial contractility and cell size in vivo in transgenic mice. Proc Natl Acad Sci USA 17:12333–12338CrossRefGoogle Scholar
  102. 102.
    Liu Tj, Lai Hc, Wu W, Chinn S, Wang PH (2001) Developing a strategy to define the effects of insulin-like growth factor-1 on gene expression profile in cardiomyocytes. Circ Res 88:1231–1238PubMedGoogle Scholar
  103. 103.
    Cook SA, Matsui T, Li L, Rosenzweig A (2002) Transcriptional effects of chronic Akt activation in the heart. J Biol Chem 277:22528–22533CrossRefPubMedGoogle Scholar
  104. 104.
    Edinger AL, Thompson CB (2002) Akt maintains cell size and survival by increasing mTOR-dependent nutrient uptake. Mol Biol Cell 13:2276–2288PubMedGoogle Scholar
  105. 105.
    Nebigil CG, Etienne N, Messaddeq N, Maroteaux L (2003) Serotonin is a novel survival factor of cardiomyocytes: mitochondria as a target of 5-HT2B receptor signaling. FASEB J 17:1373–1375PubMedGoogle Scholar
  106. 106.
    Matsui T, Tao J, del Monte F, Lee KH, 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 104:330–335PubMedGoogle Scholar
  107. 107.
    Krieg T, Qin Q, McIntosh EC, Cohen MV, Downey JM (2002) ACh and adenosine activate PI3-kinase in rabbit hearts through transactivation of receptor tyrosine kinases. Am J Physiol Heart Circ Physiol 283:H2322–H2330PubMedGoogle Scholar
  108. 108.
    Li Y, Sato T (2001) Dual signaling via protein kinase C and phosphatidylinositol 3’-kinase/Akt contributes to bradykinin B2 receptor-induced cardioprotection in guinea pig hearts. J Mol Cell Cardiol 33:2047–2053CrossRefPubMedGoogle Scholar
  109. 109.
    Chandel NS, Schumacker PT (2000) Cellular oxygen sensing by mitochondria: old questions, new insight. J Appl Physiol 88:1880–1889Google Scholar
  110. 110.
    Duranteau J, Chandel NS, Kulisz A, Shao Z, Schumacker PT (19980 Intracellular signaling by reactive oxygen species during hypoxia in cardiomyocytes. J Biol Chem 273:11619–11624CrossRefGoogle Scholar
  111. 111.
    Kacimi R, Long CS, Karliner JS (1997) Chronic hypoxia modulates the interleukin-1_stimulated inducible nitric oxide synthase pathway in cardiac myocytes. Circulation 96:1937–1943PubMedGoogle Scholar
  112. 112.
    French S, Giulivi C, Balaban RS (2001) Nitric oxide synthase in porcine heart mitochondria: evidence for low physiological activity. Am J Physiol Heart Circ Physiol 280:H2863–H2867PubMedGoogle Scholar
  113. 113.
    Kanai AJ, Pearce LL, Clemens PR, Birder LA, VanBibber MM, Choi SY, de Groat WC, Peterson J (2001) Identification of a neuronal nitric oxide synthase in isolated cardiac mitochondria using electrochemical detection. Proc Natl Acad Sci USA 98:14126–14131CrossRefPubMedGoogle Scholar
  114. 114.
    Kulisz A, Chen N, Chandel NS, Shao Z, Schumacker PT (2002) Mitochondrial ROS initiate phosphorylation of p38 MAP kinase during hypoxia in cardiomyocytes. Am J Physiol Lung Cell Mol Physiol 282:L1324–L1329PubMedGoogle Scholar
  115. 115.
    Enomoto N, Koshikawa N, Gassmann M, Hayashi J, Takenaga K (2002) Hypoxic induction of hypoxia-inducible factor-1alpha and oxygen-regulated gene expression in mitochondrial DNA-depleted HeLa cells. Biochem Biophys Res Commun 297:346–352CrossRefPubMedGoogle Scholar
  116. 116.
    Lopaschuk GD, Collins-Nakai RL, Itoi T (1992) Developmental changes in energy substrate use by the heart. Cardiovasc Res 26:1172–1180PubMedGoogle Scholar
  117. 117.
    Bonnet D, Martin D, De Lonlay P, Villain E, Jouvet P, Rabier D, Brivet M, Saudubray JM (1999) Arrhythmias and conduction defects as presenting symptoms of fatty acid oxidation disorders in children. Circulation 100:2248–2253PubMedGoogle Scholar
  118. 118.
    Lanni A, De Felice M, Lombardi A, Moreno M, Fleury C, Ricquier D, Goglia F (1997) Induction of UCP2 mRNA by thyroid hormones in rat heart. FEBS Lett 418:171–174CrossRefPubMedGoogle Scholar
  119. 119.
    Boehm EA, Jones BE, Radda GK, Veech RL, Clarke K (2001) Increased uncoupling proteins and decreased efficiency in palmitate-perfused hyperthyroid rat heart. Am J Physiol Heart Circ Physiol 280:H977–H983PubMedGoogle Scholar
  120. 120.
    Young ME, Patil S, Ying J, Depre C, Ahuja HS, Shipley GL, Stepkowski SM, Davies PJ, Taegtmeyer H (2001) Uncoupling protein 3 transcription is regulated by peroxisome proliferator-activated receptor (alpha) in the adult rodent heart. FASEB J 15:833–845PubMedGoogle Scholar
  121. 121.
    Sanguinetti MC, Bennett PB (2003) Antiarrhythmic drug target choices and screening. Circ Res 93:491–499CrossRefPubMedGoogle Scholar
  122. 122.
    Ito H, Taniyama Y, Iwakura K, Nishikawa N, Mauyama T, Kuzuya T, Hori M, Higashino Y, Fujii K, Minamino T (1999) Intravenous nicorandil can preserve microvascular integrity and myocardial viability in patients with reperfused anterior wall myocardial infarction. J Am Coll Cardiol 33:654–660CrossRefPubMedGoogle Scholar
  123. 123.
    Shoffner JM, Wallace DC (1994) Oxidative phosphorylation diseases and mito-chondrial DNA mutations: diagnosis and treatment. Annu Rev Nutr 14:535–568CrossRefPubMedGoogle Scholar
  124. 124.
    Rustin P, von Kleist-Retzow JC, Chantrel-Groussard K, Sidi D, Munnich A, Rotig A (1999) Effect of idebenone on cardiomyopathy in Friedreich’s ataxia: a preliminary study. Lancet 354:477–479CrossRefPubMedGoogle Scholar
  125. 125.
    Wallhaus TR, Taylor M, DeGrado TR, Russell DC, Stanko P, Nickles RJ (2001) Myocardial free fatty acid and glucose use after carvedilol treatment in patients with congestive heart failure. Circulation 103:2441–2446PubMedGoogle Scholar
  126. 126.
    Pollitt RJ (1995) Disorders of mitochondrial long-chain fatty acid oxidation. J Inherit Metab Dis 18:473–490PubMedGoogle Scholar
  127. 127.
    Pepe S, Tsuchiya N, Lakatta EG, Hansford RG (1999) PUFA and aging modulate cardiac mitochondrial membrane lipid composition and Ca2+ activation of PDH. Am J Physiol 276:H149–H158PubMedGoogle Scholar
  128. 128.
    Ennis IL, Li RA, Murphy AM, Marban E, Nuss HB (2002) Dual gene therapy with SERCA1 and Kir2.1 abbreviates excitation without suppressing contractility. J Clin Invest 109:393–400CrossRefPubMedGoogle Scholar
  129. 129.
    Beltrami AP, Barlucchi L, Torella D, Baker M, Limana F, Chimenti S, Kasahara H, Rota M, Musso E, Urbanek K, Leri A, Kajstura J, Nadal-Ginard B, Anversa P (2003) Adult cardiac stem cells are multipotent and support myocardial regeneration. Cell 114:763–776Google Scholar

Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  1. 1.Molecular Cardiology and Neuromuscular InstituteHighland ParkUSA

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