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The Interplay between Pro-Death and Pro-Survival Signaling Pathways in Myocardial Ischemia/Reperfusion Injury: Apoptosis Meets Autophagy

  • Anne Hamacher-Brady
  • Nathan Ryan Brady
  • Roberta Anne Gottlieb
Review

Abstract

Introduction

Programmed cell death of cardiac myocytes occurs following a bout of ischemia/reperfusion (I/R), which results in reduced function of the heart. Numerous studies, including in vivo, have shown that cell death occurs via necrosis and apoptosis following I/R. Recently, autophagy has emerged as a powerful mediator of programmed cell death, either opposing or enhancing apoptosis, or acting as an alternative form of programmed cell death distinct from apoptosis.

Aim

Here we review the apoptotic and autophagic signaling pathways, their influences on each other, and we discuss the relevance of autophagy in the heart.

Key words

apoptosis autophagy mitochondria GFP-LC3 

References

  1. 1.
    Acehan D, Jiang X, Morgan DG, Heuser JE, Wang X, Akey CW. Three-dimensional structure of the apoptosome: implications for assembly, procaspase-9 binding, and activation. Mol Cell 2002;9:423–32.PubMedGoogle Scholar
  2. 2.
    Akazawa H, Komazaki S, Shimomura H, Terasaki F, Zou Y, Takano H, et al. Diphtheria toxin-induced autophagic cardiomyocyte death plays a pathogenic role in mouse model of heart failure. J Biol Chem 2004;279:41095–103.PubMedGoogle Scholar
  3. 3.
    Ambrosio G, Zweier JL, Duilio C, Kuppusamy P, Santoro G, Elia PP, et al. Evidence that mitochondrial respiration is a source of potentially toxic oxygen free radicals in intact rabbit hearts subjected to ischemia and reflow. J Biol Chem 1993;268:18532–41.PubMedGoogle Scholar
  4. 4.
    Antonsson B. Mitochondria and the Bcl-2 family proteins in apoptosis signaling pathways. Mol Cell Biochem 2004;256–257:141–55.PubMedGoogle Scholar
  5. 5.
    Aplin A, Jasionowski T, Tuttle DL, Lenk SE, Dunn WA, Jr. Cytoskeletal elements are required for the formation and maturation of autophagic vacuoles. J Cell Physiol 1992;152:458–66.PubMedGoogle Scholar
  6. 6.
    Ashkenazi A, Dixit VM. Death receptors: signaling and modulation. Science 1998;281:1305–8.PubMedGoogle Scholar
  7. 7.
    Bagchi D, Wetscher GJ, Bagchi M, Hinder PR, Perdikis G, Stohs SJ, et al. Interrelationship between cellular calcium homeostasis and free radical generation in myocardial reperfusion injury. Chem Biol Interact 1997;104:65–85.PubMedGoogle Scholar
  8. 8.
    Baines CP, Kaiser RA, Purcell NH, Blair NS, Osinska H, Hambleton MA, et al. Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death. Nature 2005;434:658–62.PubMedGoogle Scholar
  9. 9.
    Bernardi P, Scorrano L, Colonna R, Petronilli V, Di Lisa F. Mitochondria and cell death. Mechanistic aspects and methodological issues. Eur J Biochem 1999;264:687–701.PubMedGoogle Scholar
  10. 10.
    Bers DM. Calcium fluxes involved in control of cardiac myocyte contraction. Circ Res 2000;87:275–81.PubMedGoogle Scholar
  11. 11.
    Bidere N, Lorenzo HK, Carmona S, Laforge M, Harper F, Dumont C, et al. Cathepsin D triggers Bax activation, resulting in selective apoptosis-inducing factor (AIF) relocation in T lymphocytes entering the early commitment phase to apoptosis. J Biol Chem 2003;278:31401–11.PubMedGoogle Scholar
  12. 12.
    Blommaart EF, Luiken JJ, Blommaart PJ, Van Woerkom GM, Meijer AJ. Phosphorylation of ribosomal protein S6 is inhibitory for autophagy in isolated rat hepatocytes. J Biol Chem 1995;270:2320–6.PubMedGoogle Scholar
  13. 13.
    Borutaite V, Jekabsone A, Morkuniene R, Brown GC. Inhibition of mitochondrial permeability transition prevents mitochondrial dysfunction, cytochrome c release and apoptosis induced by heart ischemia. J Mol Cell Cardiol 2003;35:357–66.PubMedGoogle Scholar
  14. 14.
    Boveris A, Oshino N, Chance B. The cellular production of hydrogen peroxide. Biochem J 1972;128:617–30.PubMedGoogle Scholar
  15. 15.
    Boya P, Gonzalez-Polo RA, Casares N, Perfettini JL, Dessen P, Larochette N, et al. Inhibition of macroautophagy triggers apoptosis. Mol Cell Biol 2005;25:1025–40.PubMedGoogle Scholar
  16. 16.
    Breckenridge DG, Germain M, Mathai JP, Nguyen M, Shore GC. Regulation of apoptosis by endoplasmic reticulum pathways. Oncogene 2003;22:8608–18.PubMedGoogle Scholar
  17. 17.
    Brocheriou V, Hagege AA, Oubenaissa A, Lambert M, Mallet VO, Duriez M, et al. Cardiac functional improvement by a human Bcl-2 transgene in a mouse model of ischemia/reperfusion injury. J Gene Med 2000;2:326–33.PubMedGoogle Scholar
  18. 18.
    Bruick RK. Expression of the gene encoding the proapoptotic Nip3 protein is induced by hypoxia. Proc Natl Acad Sci USA 2000;97:9082–7.PubMedGoogle Scholar
  19. 19.
    Brunk UT, Terman A. The mitochondrial-lysosomal axis theory of aging: accumulation of damaged mitochondria as a result of imperfect autophagocytosis. Eur J Biochem 2002;269:1996–2002.PubMedGoogle Scholar
  20. 20.
    Bursch W. The autophagosomal-lysosomal compartment in programmed cell death. Cell Death Differ 2001;8:569–81.PubMedGoogle Scholar
  21. 21.
    Cai Z, Manalo DJ, Wei G, Rodriguez ER, Fox-Talbot K, Lu H, et al. Hearts from rodents exposed to intermittent hypoxia or erythropoietin are protected against ischemia–reperfusion injury. Circulation 2003;108:79–85.PubMedGoogle Scholar
  22. 22.
    Calvillo L, Masson S, Salio M, Pollicino L, De Angelis N, Fiordaliso F, et al. In vivo cardioprotection by N-acetylcysteine and isosorbide 5-mononitrate in a rat model of ischemia–reperfusion. Cardiovasc Drugs Ther 2003;17:199–208.PubMedGoogle Scholar
  23. 23.
    Canu N, Tufi R, Serafino AL, Amadoro G, Ciotti MT, Calissano P. Role of the autophagic-lysosomal system on low potassium-induced apoptosis in cultured cerebellar granule cells. J Neurochem 2005;92:1228–42.PubMedGoogle Scholar
  24. 24.
    Chang L, Chiang SH, Saltiel AR. Insulin signaling and the regulation of glucose transport. Mol Med 2004;10:65–71.PubMedGoogle Scholar
  25. 25.
    Chen G, Ray R, Dubik D, Shi L, Cizeau J, Bleackley RC, et al. The E1B 19K/Bcl-2-binding protein Nip3 is a dimeric mitochondrial protein that activates apoptosis. J Exp Med 1997;186:1975–83.PubMedGoogle Scholar
  26. 26.
    Chen M, He H, Zhan S, Krajewski S, Reed JC, Gottlieb RA. Bid is cleaved by calpain to an active fragment in vitro and during myocardial ischemia/reperfusion. J Biol Chem 2001;276:30724–8.PubMedGoogle Scholar
  27. 27.
    Cheng EH, Wei MC, Weiler S, Flavell RA, Mak TW, Lindsten T, et al. BCL-2, BCL-X(L) sequester BH3 domain-only molecules preventing BAX- and BAK-mediated mitochondrial apoptosis. Mol Cell 2001;8:705–11.PubMedGoogle Scholar
  28. 28.
    Chiesi M, Longoni S, Limbruno U. Cardiac alpha-crystallin. III. Involvement during heart ischemia. Mol Cell Biochem 1990;97:129–36.PubMedGoogle Scholar
  29. 29.
    Chinnaiyan AM, O’Rourke K, Tewari M, Dixit VM. FADD, a novel death domain-containing protein, interacts with the death domain of Fas and initiates apoptosis. Cell 1995;81:505–12.PubMedGoogle Scholar
  30. 30.
    Cirman T, Oresic K, Mazovec GD, Turk V, Reed JC, Myers RM, et al. Selective disruption of lysosomes in HeLa cells triggers apoptosis mediated by cleavage of Bid by multiple papain-like lysosomal cathepsins. J Biol Chem 2004;279:3578–87.PubMedGoogle Scholar
  31. 31.
    Claycomb WC, Lanson NA Jr, Stallworth BS, Egeland DB, Delcarpio JB, Bahinski A, et al. HL-1 cells: a cardiac muscle cell line that contracts and retains phenotypic characteristics of the adult cardiomyocyte. Proc Natl Acad Sci USA 1998;95:2979–84.PubMedGoogle Scholar
  32. 32.
    Codogno P, Meijer AJ. Autophagy and signaling: their role in cell survival and cell death. Cell Death Differ 2005;12 Suppl 2:1509–18.PubMedGoogle Scholar
  33. 33.
    Cory S, Adams JM. The Bcl2 family: regulators of the cellular life-or-death switch. Nat Rev Cancer 2002;2: 647–56.PubMedGoogle Scholar
  34. 34.
    Crompton M. Mitochondrial intermembrane junctional complexes and their role in cell death. J Physiol 2000;529 Pt 1:11–21.PubMedGoogle Scholar
  35. 35.
    Crow MT, Mani K, Nam YJ, Kitsis RN. The mitochondrial death pathway and cardiac myocyte apoptosis. Circ Res 2004;95:957–70.PubMedGoogle Scholar
  36. 36.
    Cuervo AM. Autophagy: many paths to the same end. Mol Cell Biochem 2004;263:55–72.PubMedGoogle Scholar
  37. 37.
    Cuervo AM, Dice JF. A receptor for the selective uptake and degradation of proteins by lysosomes. Science 1996;273:501–3.PubMedGoogle Scholar
  38. 38.
    Daido S, Kanzawa T, Yamamoto A, Takeuchi H, Kondo Y, Kondo S. Pivotal role of the cell death factor BNIP3 in ceramide-induced autophagic cell death in malignant glioma cells. Cancer Res 2004;64:4286–93.PubMedGoogle Scholar
  39. 39.
    De Giorgi F, Lartigue L, Bauer MK, Schubert A, Grimm S, Hanson GT, et al. The permeability transition pore signals apoptosis by directing Bax translocation and multimerization. FASEB J 2002;16:607–9.PubMedGoogle Scholar
  40. 40.
    Decker RS, Poole AR, Griffin EE, Dingle JT, Wildenthal K. Altered distribution of lysosomal cathepsin D in ischemic myocardium. J Clin Invest 1977;59:911–21.PubMedCrossRefGoogle Scholar
  41. 41.
    Decker RS, Wildenthal K. Lysosomal alterations in hypoxic and reoxygenated hearts. I. Ultrastructural and cytochemical changes. Am J Pathol 1980;98:425–44.PubMedGoogle Scholar
  42. 42.
    Depre C, Kim SJ, John AS, Huang Y, Rimoldi OE, Pepper JR, et al. Program of cell survival underlying human and experimental hibernating myocardium. Circ Res 2004;95:433–40.PubMedGoogle Scholar
  43. 43.
    Desagher S, Martinou JC. Mitochondria as the central control point of apoptosis. Trends Cell Biol 2000;10:369–77.PubMedGoogle Scholar
  44. 44.
    Du C, Fang M, Li Y, Li L, Wang X. Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition. Cell 2000;102:33–42.PubMedGoogle Scholar
  45. 45.
    Duchen MR. Mitochondria and Ca(2+)in cell physiology and pathophysiology. Cell Calcium 2000;28:339–48.PubMedGoogle Scholar
  46. 46.
    Ellsworth DL, Sholinsky P, Jaquish C, Fabsitz RR, Manolio TA. Coronary heart disease. At the interface of molecular genetics and preventive medicine. Am J Prev Med 1999;16: 122–33.PubMedGoogle Scholar
  47. 47.
    Elmore SP, Qian T, Grissom SF, Lemasters JJ. The mitochondrial permeability transition initiates autophagy in rat hepatocytes. FASEB J 2001;15:2286–7.PubMedGoogle Scholar
  48. 48.
    Elsasser A, Vogt AM, Nef H, Kostin S, Mollmann H, Skwara W, et al. Human hibernating myocardium is jeopardized by apoptotic and autophagic cell death. J Am Coll Cardiol 2004;43:2191–9.PubMedGoogle Scholar
  49. 49.
    Esposti MD. The roles of Bid. Apoptosis 2002;7:433–40.PubMedGoogle Scholar
  50. 50.
    George MD, Baba M, Scott SV, Mizushima N, Garrison BS, Ohsumi Y, et al. Apg5p functions in the sequestration step in the cytoplasm-to-vacuole targeting and macroautophagy pathways. Mol Biol Cell 2000;11:969–82.PubMedGoogle Scholar
  51. 51.
    Goping IS, Gross A, Lavoie JN, Nguyen M, Jemmerson R, Roth K, et al. Regulated targeting of BAX to mitochondria. J Cell Biol 1998;143:207–15.PubMedGoogle Scholar
  52. 52.
    Gordon PB, Hoyvik H, Seglen PO. Prelysosomal and lysosomal connections between autophagy and endocytosis. Biochem J 1992;283 Pt 2:361–9.PubMedGoogle Scholar
  53. 53.
    Gottlieb RA, Engler RL. Apoptosis in myocardial ischemia–reperfusion. Ann NY Acad Sci 1999;874:412–26.PubMedGoogle Scholar
  54. 54.
    Grand RJ, Milner AE, Mustoe T, Johnson GD, Owen D, Grant ML, et al. A novel protein expressed in mammalian cells undergoing apoptosis. Exp Cell Res 1995;218:439–51.PubMedGoogle Scholar
  55. 55.
    Green DR, Reed JC. Mitochondria and apoptosis. Science 1998;281:1309–12.PubMedGoogle Scholar
  56. 56.
    Gross ER, Hsu AK, Gross GJ. Opioid-induced cardioprotection occurs via glycogen synthase kinase beta inhibition during reperfusion in intact rat hearts. Circ Res 2004;94:960–6.PubMedGoogle Scholar
  57. 57.
    Guicciardi ME, Bronk SF, Werneburg NW, Yin XM, Gores GJ. Bid is upstream of lysosome-mediated caspase 2 activation in tumor necrosis factor alpha-induced hepatocyte apoptosis. Gastroenterology 2005;129:269–84.PubMedGoogle Scholar
  58. 58.
    Gustafsson AB, Gottlieb RA. Mechanisms of apoptosis in the heart. J Clin Immunol 2003;23:447–59.PubMedGoogle Scholar
  59. 59.
    Gustafsson AB, Sayen MR, Williams SD, Crow MT, Gottlieb RA. TAT protein transduction into isolated perfused hearts: TAT-apoptosis repressor with caspase recruitment domain is cardioprotective. Circulation 2002;106:735–9.PubMedGoogle Scholar
  60. 60.
    Gutierrez MG, Master SS, Singh SB, Taylor GA, Colombo MI, Deretic V. Autophagy is a defense mechanism inhibiting BCG and Mycobacterium tuberculosis survival in infected macrophages. Cell 2004a;119:753–66.PubMedGoogle Scholar
  61. 61.
    Gutierrez MG, Munafo DB, Beron W, Colombo MI. Rab7 is required for the normal progression of the autophagic pathway in mammalian cells. J Cell Sci 2004b;117:2687–97.PubMedGoogle Scholar
  62. 62.
    Halestrap AP. Calcium, mitochondria and reperfusion injury: a pore way to die. Biochem Soc Trans 2006;34:232–7.PubMedGoogle Scholar
  63. 63.
    Halestrap AP, Clarke SJ, Javadov SA. Mitochondrial permeability transition pore opening during myocardial reperfusion—a target for cardioprotection. Cardiovasc Res 2004;61:372–85.PubMedGoogle Scholar
  64. 64.
    Hamacher-Brady A, Brady NR, Logue SE, Sayen MR, Jinno M, Kirshenbaum LA, et al. Response to myocardial ischemia/reperfusion injury involves Bnip3 and autophagy. Cell Death Differ 2006. DOI 10.1038/sj.cdd.4401936.Google Scholar
  65. 65.
    Hanada M, Feng J, Hemmings BA. Structure, regulation and function of PKB/AKT—a major therapeutic target. Biochim Biophys Acta 2004;1697:3–16.PubMedGoogle Scholar
  66. 66.
    Hausenloy DJ, Duchen MR, Yellon DM. Inhibiting mitochondrial permeability transition pore opening at reperfusion protects against ischaemia–reperfusion injury. Cardiovasc Res 2003;60:617–25.PubMedGoogle Scholar
  67. 67.
    Hochhauser E, Kivity S, Offen D, Maulik N, Otani H, Barhum Y, et al. Bax ablation protects against myocardial ischemia–reperfusion injury in transgenic mice. Am J Physiol Heart Circ Physiol 2003;284:H2351–9.PubMedGoogle Scholar
  68. 68.
    Horvath J, Ketelsen UP, Geibel-Zehender A, Boehm N, Olbrich H, Korinthenberg R, et al. Identification of a novel LAMP2 mutation responsible for X-chromosomal dominant Danon disease. Neuropediatrics 2003;34:270–3.PubMedGoogle Scholar
  69. 69.
    Hsu H, Xiong J, Goeddel DV. The TNF receptor 1-associated protein TRADD signals cell death and NF-kappa B activation. Cell 1995;81:495–504.PubMedGoogle Scholar
  70. 70.
    Huang J, Nakamura K, Ito Y, Uzuka T, Morikawa M, Hirai S, et al. Bcl-xL gene transfer inhibits Bax translocation and prolongs cardiac cold preservation time in rats. Circulation 2005;112:76–83.PubMedGoogle Scholar
  71. 71.
    Imahashi K, Schneider MD, Steenbergen C, Murphy E. Transgenic expression of Bcl-2 modulates energy metabolism, prevents cytosolic acidification during ischemia, and reduces ischemia/reperfusion injury. Circ Res 2004;95:734–41.PubMedGoogle Scholar
  72. 72.
    Inagaki K, Hahn HS, Dorn GW 2nd, Mochly-Rosen D. Additive protection of the ischemic heart ex vivo by combined treatment with delta-protein kinase C inhibitor and epsilon-protein kinase C activator. Circulation 2003;108:869–75.PubMedGoogle Scholar
  73. 73.
    Ishii T, Sakurai T, Usami H, Uchida K. Oxidative modification of proteasome: identification of an oxidation-sensitive subunit in 26 S proteasome. Biochemistry 2005;44:13893–901.PubMedGoogle Scholar
  74. 74.
    Jager S, Bucci C, Tanida I, Ueno T, Kominami E, Saftig P, et al. Role for Rab7 in maturation of late autophagic vacuoles. J Cell Sci 2004;117:4837–48.PubMedGoogle Scholar
  75. 75.
    Juhasz G, Neufeld TP. Autophagy: a forty-year search for a missing membrane source. PLoS Biol 2006;4:e36.PubMedGoogle Scholar
  76. 76.
    Juhaszova M, Rabuel C, Zorov DB, Lakatta EG, Sollott SJ. Protection in the aged heart: preventing the heart-break of old age? Cardiovasc Res 2005;66:233–44.PubMedGoogle Scholar
  77. 77.
    Kabeya Y, Mizushima N, Ueno T, Yamamoto A, Kirisako T, Noda T, et al. LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing. EMBO J 2000;19:5720–8.PubMedGoogle Scholar
  78. 78.
    Kabeya Y, Mizushima N, Yamamoto A, Oshitani-Okamoto S, Ohsumi Y, Yoshimori T. LC3, GABARAP and GATE16 localize to autophagosomal membrane depending on form-II formation. J Cell Sci 2004;117:2805–12.PubMedGoogle Scholar
  79. 79.
    Kagedal K, Johansson AC, Johansson U, Heimlich G, Roberg K, Wang NS, et al. Lysosomal membrane permeabilization during apoptosis-involvement of Bax? Int J Exp Pathol 2005;86:309–21.PubMedGoogle Scholar
  80. 80.
    Kajstura J, Cheng W, Reiss K, Clark WA, Sonnenblick EH, Krajewski S, et al. Apoptotic and necrotic myocyte cell deaths are independent contributing variables of infarct size in rats. Lab Invest 1996;74:86–107.PubMedGoogle Scholar
  81. 81.
    Kanzawa T, Zhang L, Xiao L, Germano IM, Kondo Y, Kondo S. Arsenic trioxide induces autophagic cell death in malignant glioma cells by upregulation of mitochondrial cell death protein BNIP3. Oncogene 2005;24:980–91.PubMedGoogle Scholar
  82. 82.
    Kelekar A, Thompson CB. Bcl-2-family proteins: the role of the BH3 domain in apoptosis. Trends Cell Biol 1998;8:324–30.PubMedGoogle Scholar
  83. 83.
    Kihara A, Kabeya Y, Ohsumi Y, Yoshimori T. Beclin-phosphatidylinositol 3-kinase complex functions at the trans-Golgi network. EMBO Rep 2001a;2:330–5.PubMedGoogle Scholar
  84. 84.
    Kihara A, Noda T, Ishihara N, Ohsumi Y. Two distinct Vps34 phosphatidylinositol 3-kinase complexes function in autophagy and carboxypeptidase Y sorting in Saccharomyces cerevisiae. J Cell Biol 2001b;152:519–30.PubMedGoogle Scholar
  85. 85.
    Kim JS, He L, Lemasters JJ. Mitochondrial permeability transition: a common pathway to necrosis and apoptosis. Biochem Biophys Res Commun 2003;304:463–70.PubMedGoogle Scholar
  86. 86.
    Kim JS, Jin Y, Lemasters JJ. Reactive oxygen species, but not Ca2+, triger pH- and mitochondrial permeability transition-dependent death of adult rat myocytes after ischemia/reperfusion. Am J Physiol Heart Circ Physiol 2006;290(5):H2024–34.Google Scholar
  87. 87.
    Kimura H, Shintani-Ishida K, Nakajima M, Liu S, Matsumoto K, Yoshida K. Ischemic preconditioning or p38 MAP kinase inhibition attenuates myocardial TNF alpha production and mitochondria damage in brief myocardial ischemia. Life Sci 2006;78:1901–10.PubMedGoogle Scholar
  88. 88.
    Kirisako T, Baba M, Ishihara N, Miyazawa K, Ohsumi M, Yoshimori T, et al. Formation process of autophagosome is traced with Apg8/Aut7p in yeast. J Cell Biol 1999;147:435–46.PubMedGoogle Scholar
  89. 89.
    Kirisako T, Ichimura Y, Okada H, Kabeya Y, Mizushima N, Yoshimori T, et al. The reversible modification regulates the membrane-binding state of Apg8/Aut7 essential for autophagy and the cytoplasm to vacuole targeting pathway. J Cell Biol 2000;151:263–76.PubMedGoogle Scholar
  90. 90.
    Klionsky DJ, Emr SD. Autophagy as a regulated pathway of cellular degradation. Science 2000;290:1717–21.PubMedGoogle Scholar
  91. 91.
    Knaapen MW, Davies MJ, De Bie M, Haven AJ, Martinet W, Kockx MM. Apoptotic versus autophagic cell death in heart failure. Cardiovasc Res 2001;51:304–12.PubMedGoogle Scholar
  92. 92.
    Kochl R, Hu XW, Chan EY, Tooze SA. Microtubules facilitate autophagosome formation and fusion of autophagosomes with endosomes. Traffic 2006;7:129–45.PubMedGoogle Scholar
  93. 93.
    Komatsu M, Waguri S, Chiba T, Murata S, Iwata JI, Tanida I, et al. Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 2006; 441(7095):880–4.PubMedGoogle Scholar
  94. 94.
    Kouno T, Mizuguchi M, Tanida I, Ueno T, Kanematsu T, Mori Y, et al. Solution structure of microtubule-associated protein light chain 3 and identification of its functional subdomains. J Biol Chem 2005;280:24610–7.PubMedGoogle Scholar
  95. 95.
    Krajewski S, Tanaka S, Takayama S, Schibler MJ, Fenton W, Reed JC. Investigation of the subcellular distribution of the bcl-2 oncoprotein: residence in the nuclear envelope, endoplasmic reticulum, and outer mitochondrial membranes. Cancer Res 1993;53:4701–14.PubMedGoogle Scholar
  96. 96.
    Kubasiak LA, Hernandez OM, Bishopric NH, Webster KA. Hypoxia and acidosis activate cardiac myocyte death through the Bcl-2 family protein BNIP3. Proc Natl Acad Sci USA 2002;99:12825–30.PubMedGoogle Scholar
  97. 97.
    Kuma A, Hatano M, Matsui M, Yamamoto A, Nakaya H, Yoshimori T, et al. The role of autophagy during the early neonatal starvation period. Nature 2004;432:1032–6.PubMedGoogle Scholar
  98. 98.
    Lamparska-Przybysz M, Gajkowska B, Motyl T. Cathepsins and BID are involved in the molecular switch between apoptosis and autophagy in breast cancer MCF-7 cells exposed to camptothecin. J Physiol Pharmacol 2005;56 Suppl 3:159–79.PubMedGoogle Scholar
  99. 99.
    Lee P, Sata M, Lefer DJ, Factor SM, Walsh K, Kitsis RN. Fas pathway is a critical mediator of cardiac myocyte death and MI during ischemia–reperfusion in vivo. Am J Physiol Heart Circ Physiol 2003;284:H456–63.PubMedGoogle Scholar
  100. 100.
    Lefer AM, Tsao P, Aoki N, Palladino MA Jr. Mediation of cardioprotection by transforming growth factor-beta. Science 1990;249:61–4.PubMedGoogle Scholar
  101. 101.
    Levraut J, Iwase H, Shao ZH, Vanden Hoek TL, Schumacker PT. Cell death during ischemia: relationship to mitochondrial depolarization and ROS generation. Am J Physiol Heart Circ Physiol 2003;284:H549–58.PubMedGoogle Scholar
  102. 102.
    Leyssens A, Nowicky AV, Patterson L, Crompton M, Duchen MR. The relationship between mitochondrial state, ATP hydrolysis, [Mg2+]i and [Ca2+]i studied in isolated rat cardiomyocytes. J Physiol (Lond) 1996;496:111–28.Google Scholar
  103. 103.
    Li H, Zhu H, Xu CJ, Yuan J. Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell 1998;94:491–501.PubMedGoogle Scholar
  104. 104.
    Liang XH, Jackson S, Seaman M, Brown K, Kempkes B, Hibshoosh H, et al. Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature 1999;402:672–6.PubMedGoogle Scholar
  105. 105.
    Liang XH, Kleeman LK, Jiang HH, Gordon G, Goldman JE, Berry G, et al. Protection against fatal Sindbis virus encephalitis by beclin, a novel Bcl-2-interacting protein. J Virol 1998;72:8586–96.PubMedGoogle Scholar
  106. 106.
    Liang XH, Yu J, Brown K, Levine B. Beclin 1 contains a leucine-rich nuclear export signal that is required for its autophagy and tumor suppressor function. Cancer Res 2001;61:3443–9.PubMedGoogle Scholar
  107. 107.
    Lim ML, Lum MG, Hansen TM, Roucou X, Nagley P. On the release of cytochrome c from mitochondria during cell death signaling. J Biomed Sci 2002;9:488–506.PubMedGoogle Scholar
  108. 108.
    Liu J, Chen Q, Huang W, Horak KM, Zheng H, Mestril R, et al. Impairment of the ubiquitin-proteasome system in desminopathy mouse hearts. FASEB J 2006;20:362–4.PubMedGoogle Scholar
  109. 109.
    Lundberg KC, Szweda LI. Initiation of mitochondrial-mediated apoptosis during cardiac reperfusion. Arch Biochem Biophys 2004;432:50–7.PubMedGoogle Scholar
  110. 110.
    Marin MC, Fernandez A, Bick RJ, Brisbay S, Buja LM, Snuggs M, et al. Apoptosis suppression by bcl-2 is correlated with the regulation of nuclear and cytosolic Ca2+. Oncogene 1996;12:2259–66.PubMedGoogle Scholar
  111. 111.
    Marino G, Uria JA, Puente XS, Quesada V, Bordallo J, Lopez-Otin C. Human autophagins, a family of cysteine proteinases potentially implicated in cell degradation by autophagy. J Biol Chem 2003;278:3671–8.PubMedGoogle Scholar
  112. 112.
    Masaki R, Saito T, Yamada K, Ohtani-Kaneko R. Accumulation of phosphorylated neurofilaments and increase in apoptosis-specific protein and phosphorylated c-Jun induced by proteasome inhibitors. J Neurosci Res 2000;62:75–83.PubMedGoogle Scholar
  113. 113.
    Matsumura K, Jeremy RW, Schaper J, Becker LC. Progression of myocardial necrosis during reperfusion of ischemic myocardium. Circulation 1998;97:795–804.PubMedGoogle Scholar
  114. 114.
    Miyata S, Takemura G, Kawase Y, Li Y, Okada H, Maruyama R, et al. Autophagic cardiomyocyte death in cardiomyopathic hamsters and its prevention by granulocyte colony-stimulating factor. Am J Pathol 2006;168:386–97.PubMedGoogle Scholar
  115. 115.
    Mizushima N, Noda T, Yoshimori T, Tanaka Y, Ishii T, George MD, et al. A protein conjugation system essential for autophagy. Nature 1998a;395:395–8.PubMedGoogle Scholar
  116. 116.
    Mizushima N, Sugita H, Yoshimori T, Ohsumi Y. A new protein conjugation system in human. The counterpart of the yeast Apg12p conjugation system essential for autophagy. J Biol Chem 1998b;273:33889–92.PubMedGoogle Scholar
  117. 117.
    Mizushima N, Yamamoto A, Hatano M, Kobayashi Y, Kabeya Y, Suzuki K, et al. Dissection of autophagosome formation using Apg5-deficient mouse embryonic stem cells. J Cell Biol 2001;152:657–68.PubMedGoogle Scholar
  118. 118.
    Mizushima N, Yamamoto A, Matsui M, Yoshimori T, Ohsumi Y. In vivo analysis of autophagy in response to nutrient starvation using transgenic mice expressing a fluorescent autophagosome marker. Mol Biol Cell 2004;15:1101–11.PubMedGoogle Scholar
  119. 119.
    Muzio M, Stockwell BR, Stennicke HR, Salvesen GS, Dixit VM. An induced proximity model for caspase-8 activation. J Biol Chem 1998;273:2926–30.PubMedGoogle Scholar
  120. 120.
    Narula J, Haider N, Virmani R, Disalvo TG, Kolodgie FD, Hajjar RJ, et al. Apoptosis in myocytes in end-stage heart failure. N Engl J Med 1996;335:1182–9.PubMedGoogle Scholar
  121. 121.
    Nechushtan A, Smith CL, Hsu YT, Youle RJ. Conformation of the Bax C-terminus regulates subcellular location and cell death. EMBO J 1999;18:2330–41.PubMedGoogle Scholar
  122. 122.
    Nicholson DW, Ali A, Thornberry NA, Vaillancourt JP, Ding CK, Gallant M, et al. Identification and inhibition of the ICE/CED-3 protease necessary for mammalian apoptosis. Nature 1995;376:37–43.PubMedGoogle Scholar
  123. 123.
    Noda T, Ohsumi Y. Tor, a phosphatidylinositol kinase homologue, controls autophagy in yeast. J Biol Chem 1998;273:3963-6.PubMedGoogle Scholar
  124. 124.
    Obara K, Sekito T, Ohsumi Y. Assortment of phosphatidylinositol 3-Kinase complexes-Atg14p directs association of complex I to the Pre-autophagosomal structure in Saccharomyces cerevisiae. Mol Biol Cell 2006;17:1527–39.PubMedGoogle Scholar
  125. 125.
    Olivetti G, Abbi R, Quaini F, Kajstura J, Cheng W, Nitahara JA, et al. Apoptosis in the failing human heart. N Engl J Med 1997;336:1131–41.PubMedGoogle Scholar
  126. 126.
    Oltvai ZN, Milliman CL, Korsmeyer SJ. Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell 1993;74:609–19.PubMedGoogle Scholar
  127. 127.
    Papa S, Skulachev VP. Reactive oxygen species, mitochondria, apoptosis and aging. Mol Cell Biochem 1997;174:305–19.PubMedGoogle Scholar
  128. 128.
    Pattingre S, Tassa A, Qu X, Garuti R, Liang XH, Mizushima N, et al. Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy. Cell 2005;122:927–39.PubMedGoogle Scholar
  129. 129.
    Peng C-F, Lee P, Deguzman A, Miao W, Chandra M, Shirani J, et al. Multiple independent mutations in apoptotic signaling pathways markedly decrease infarct size due to myocardial ischemia–reperfusion. Circulation 2001; Supp:II-187.Google Scholar
  130. 130.
    Petiot A, Ogier-Denis E, Blommaart EF, Meijer AJ, Codogno P. Distinct classes of phosphatidylinositol 3′-kinases are involved in signaling pathways that control macroautophagy in HT-29 cells. J Biol Chem 2000;275:992–8.PubMedGoogle Scholar
  131. 131.
    Pfeifer U, Dammrich J. Intracellular turnover and cardiac hypertrophy. Basic Res Cardiol 1986;81 Suppl 1:139–46.PubMedGoogle Scholar
  132. 132.
    Poulter N. Global risk of cardiovascular disease. Heart 2003;89 Suppl 2:ii2–5 (discussion ii35–7).PubMedGoogle Scholar
  133. 133.
    Powell SR, Wang P, Katzeff H, Shringarpure R, Teoh C, Khaliulin I, et al. Oxidized and ubiquitinated proteins may predict recovery of postischemic cardiac function: essential role of the proteasome. Antioxid Redox Signal 2005;7:538–46.PubMedGoogle Scholar
  134. 134.
    Precht TA, Phelps RA, Linseman DA, Butts BD, Le SS, Laessig TA, et al. The permeability transition pore triggers Bax translocation to mitochondria during neuronal apoptosis. Cell Death Differ 2005;12:255–65.PubMedGoogle Scholar
  135. 135.
    Priault M, Salin B, Schaeffer J, Vallette FM, Di Rago JP, Martinou JC. Impairing the bioenergetic status and the biogenesis of mitochondria triggers mitophagy in yeast. Cell Death Differ 2005.Google Scholar
  136. 136.
    Pyo JO, Jang MH, Kwon YK, Lee HJ, Jun JI, Woo HN, et al. Essential roles of Atg5 and FADD in autophagic cell death: dissection of autophagic cell death into vacuole formation and cell death. J Biol Chem 2005;280:20722–9.PubMedGoogle Scholar
  137. 137.
    Qin Y, Vanden Hoek TL, Wojcik K, Anderson T, Li CQ, Shao ZH, et al. Caspase-dependent cytochrome c release and cell death in chick cardiomyocytes after simulated ischemia–reperfusion. Am J Physiol Heart Circ Physiol 2004;286:H2280–6.PubMedGoogle Scholar
  138. 138.
    Ravikumar B, Berger Z, Vacher C, O’Kane CJ, Rubinsztein DC. Rapamycin pre-treatment protects against apoptosis. Hum Mol Genet 2006;15:1209–16.PubMedGoogle Scholar
  139. 139.
    Ravikumar B, Vacher C, Berger Z, Davies JE, Luo S, Oroz LG, et al. Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat Genet 2004;36:585–95.PubMedGoogle Scholar
  140. 140.
    Reed JC, Jurgensmeier JM, Matsuyama S. Bcl-2 family proteins and mitochondria. Biochim Biophys Acta 1998;1366:127–37.PubMedGoogle Scholar
  141. 141.
    Regula KM, Ens K, Kirshenbaum LA. Inducible expression of BNIP3 provokes mitochondrial defects and hypoxia-mediated cell death of ventricular myocytes. Circ Res 2002;91:226–31.PubMedGoogle Scholar
  142. 142.
    Rizzuto R, Bernardi P, Pozzan T. Mitochondria as all-round players of the calcium game. J Physiol 2000;529 Pt 1:37–47.PubMedGoogle Scholar
  143. 143.
    Rodriguez J, Lazebnik Y. Caspase-9 and APAF-1 form an active holoenzyme. Genes Dev 1999;13:3179–84.PubMedGoogle Scholar
  144. 144.
    Row PE, Reaves BJ, Domin J, Luzio JP, Davidson HW. Overexpression of a rat kinase-deficient phosphoinositide 3-kinase, Vps34p, inhibits cathepsin D maturation. Biochem J 2001;353:655–61.PubMedGoogle Scholar
  145. 145.
    Saeki K, Yuo A, Okuma E, Yazaki Y, Susin SA, Kroemer G, et al. Bcl-2 down-regulation causes autophagy in a caspase-independent manner in human leukemic HL60 cells. Cell Death Differ 2000;7:1263–9.PubMedGoogle Scholar
  146. 146.
    Saftig P, Tanaka Y, Lullmann-Rauch R, Von Figura K. Disease model: LAMP-2 enlightens Danon disease. Trends Mol Med 2001;7:37–9.PubMedGoogle Scholar
  147. 147.
    Saijo M, Takemura G, Koda M, Okada H, Miyata S, Ohno Y, et al. Cardiomyopathy with prominent autophagic degeneration, accompanied by an elevated plasma brain natriuretic peptide level despite the lack of overt heart failure. Intern Med 2004;43:700–3.PubMedGoogle Scholar
  148. 148.
    Saito M, Korsmeyer SJ, Schlesinger PH. BAX-dependent transport of cytochrome c reconstituted in pure liposomes. Nat Cell Biol 2000;2:553–5.PubMedGoogle Scholar
  149. 149.
    Saraste A. Morphologic criteria and detection of apoptosis. Herz 1999;24:189–95.PubMedCrossRefGoogle Scholar
  150. 150.
    Schmelzle T, Hall MN. TOR, a central controller of cell growth. Cell 2000;103:253–62.PubMedGoogle Scholar
  151. 151.
    Schmitz I, Kirchhoff S, Krammer PH. Regulation of death receptor-mediated apoptosis pathways. Int J Biochem Cell Biol 2000;32:1123–36.PubMedGoogle Scholar
  152. 152.
    Schoppet M, Ruppert V, Hofbauer LC, Henser S, Al-Fakhri N, Christ M, et al. TNF-related apoptosis-inducing ligand and its decoy receptor osteoprotegerin in nonischemic dilated cardiomyopathy. Biochem Biophys Res Commun 2005;338:1745–50.PubMedGoogle Scholar
  153. 153.
    Schu PV, Takegawa K, Fry MJ, Stack JH, Waterfield MD, Emr SD. Phosphatidylinositol 3-kinase encoded by yeast VPS34 gene essential for protein sorting. Science 1993;260:88–91.PubMedGoogle Scholar
  154. 154.
    Schumann H, Morawietz H, Hakim K, Zerkowski HR, Eschenhagen T, Holtz J, et al. Alternative splicing of the primary Fas transcript generating soluble Fas antagonists is suppressed in the failing human ventricular myocardium. Biochem Biophys Res Commun 1997;239:794–8.PubMedGoogle Scholar
  155. 155.
    Searle J, Kerr JF, Bishop CJ. Necrosis and apoptosis: distinct modes of cell death with fundamentally different significance. Pathol Annu 1982;17 Pt 2:229–59.PubMedGoogle Scholar
  156. 156.
    Sharpe JC, Arnoult D, Youle RJ. Control of mitochondrial permeability by Bcl-2 family members. Biochim Biophys Acta 2004;1644:107–13.PubMedGoogle Scholar
  157. 157.
    Shi Y. Mechanisms of caspase activation and inhibition during apoptosis. Mol Cell 2002;9:459–70.PubMedGoogle Scholar
  158. 158.
    Shibata M, Lu T, Furuya T, Degterev A, Mizushima N, Yoshimori T, et al. Regulation of intracellular accumulation of mutant Huntingtin by Beclin 1. J Biol Chem 2006.Google Scholar
  159. 159.
    Shimizu S, Kanaseki T, Mizushima N, Mizuta T, Arakawa-Kobayashi S, Thompson CB, et al. Role of Bcl-2 family proteins in a non-apoptotic programmed cell death dependent on autophagy genes. Nat Cell Biol 2004;6:1221–8.PubMedGoogle Scholar
  160. 160.
    Shimizu S, Narita M, Tsujimoto Y. Bcl-2 family proteins regulate the release of apoptogenic cytochrome c by the mitochondrial channel VDAC. Nature 1999;399:483–7.PubMedGoogle Scholar
  161. 161.
    Shimomura H, Terasaki F, Hayashi T, Kitaura Y, Isomura T, Suma H. Autophagic degeneration as a possible mechanism of myocardial cell death in dilated cardiomyopathy. Jpn Circ J 2001;65:965–8.PubMedGoogle Scholar
  162. 162.
    Shintani T, Klionsky DJ. Autophagy in health and disease: a double-edged sword. Science 2004;306:990–5.PubMedGoogle Scholar
  163. 163.
    St-Pierre J, Buckingham JA, Roebuck SJ, Brand MD. Topology of superoxide production from different sites in the mitochondrial electron transport chain. J Biol Chem 2002;277:44784–90.PubMedGoogle Scholar
  164. 164.
    Stennicke HR, Salvesen GS. Caspases—controlling intracellular signals by protease zymogen activation. Biochim Biophys Acta 2000;1477:299–306.PubMedGoogle Scholar
  165. 165.
    Stoka V, Turk B, Schendel SL, Kim TH, Cirman T, Snipas SJ, et al. Lysosomal protease pathways to apoptosis. Cleavage of bid, not pro-caspases, is the most likely route. J Biol Chem 2001;276:3149–57;101(4):281–291PubMedGoogle Scholar
  166. 166.
    Stypmann J, Janssen PM, Prestle J, Engelen MA, Kogler H, Lullmann-Rauch R, et al. LAMP-2 deficient mice show depressed cardiac contractile function without significant changes in calcium handling. Basic Res Cardiol 2006; 101(4):281–91.Google Scholar
  167. 167.
    Sun-Wada GH, Wada Y, Futai M. Lysosome and lysosome-related organelles responsible for specialized functions in higher organisms, with special emphasis on vacuolar-type proton ATPase. Cell Struct Funct 2003;28:455–63.PubMedGoogle Scholar
  168. 168.
    Susin SA, Zamzami N, Castedo M, Hirsch T, Marchetti P, Macho A, et al. Bcl-2 inhibits the mitochondrial release of an apoptogenic protease. J Exp Med 1996;184:1331–41.PubMedGoogle Scholar
  169. 169.
    Tanida I, Minematsu-Ikeguchi N, Ueno T, Kominami E. Lysosomal turnover, but not a cellular level, of endogenous LC3 is a marker for autophagy. Autophagy 2005;1:084–91.Google Scholar
  170. 170.
    Tanida I, Ueno T, Kominami E. LC3 conjugation system in mammalian autophagy. Int J Biochem Cell Biol 2004; 36:2503–18.PubMedGoogle Scholar
  171. 171.
    Tartaglia LA, Goeddel DV. Two TNF receptors. Immunol Today 1992;13:151–3.PubMedGoogle Scholar
  172. 172.
    Terman A, Dalen H, Eaton JW, Neuzil J, Brunk UT. Mitochondrial recycling and aging of cardiac myocytes: the role of autophagocytosis. Exp Gerontol 2003;38:863–76.PubMedGoogle Scholar
  173. 173.
    Terman A, Dalen H, Eaton JW, Neuzil J, Brunk UT. Aging of cardiac myocytes in culture: oxidative stress, lipofuscin accumulation, and mitochondrial turnover. Ann N Y Acad Sci 2004;1019:70–7.PubMedGoogle Scholar
  174. 174.
    Tewari M, Quan LT, O’Rourke K, Desnoyers S, Zeng Z, Beidler DR, et al. Yama/CPP32 beta, a mammalian homolog of CED-3, is a CrmA-inhibitable protease that cleaves the death substrate poly(ADP-ribose) polymerase. Cell 1995;81:801–9.PubMedGoogle Scholar
  175. 175.
    Thom T, Haase N, Rosamond W, Howard VJ, Rumsfeld J, Manolio T, et al. Heart disease and stroke statistics—2006 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 2006;113:e85–151.PubMedGoogle Scholar
  176. 176.
    Thornberry NA, Lazebnik Y. Caspases: enemies within. Science 1998;281:1312–6.PubMedGoogle Scholar
  177. 177.
    Turrens JF, Alexandre A, Lehninger AL. Ubisemiquinone is the electron donor for superoxide formation by complex III of heart mitochondria. Arch Biochem Biophys 1985;237:408–14.PubMedGoogle Scholar
  178. 178.
    Turrens JF, Boveris A. Generation of superoxide anion by the NADH dehydrogenase of bovine heart mitochondria. Biochem J 1980;191:421–7.PubMedGoogle Scholar
  179. 179.
    Uchiyama Y. Autophagic cell death and its execution by lysosomal cathepsins. Arch Histol Cytol 2001;64:233–46.PubMedGoogle Scholar
  180. 180.
    Vande Velde C, Cizeau J, Dubik D, Alimonti J, Brown T, Israels S, et al. BNIP3 and genetic control of necrosis-like cell death through the mitochondrial permeability transition pore. Mol Cell Biol 2000;20:5454–68.Google Scholar
  181. 181.
    Vanden Hoek TL, Becker LB, Shao Z, Li C, Schumacker PT. Reactive oxygen species released from mitochondria during brief hypoxia induce preconditioning in cardiomyocytes. J Biol Chem 1998;273:18092–8.Google Scholar
  182. 182.
    Verhagen AM, Ekert PG, Pakusch M, Silke J, Connolly LM, Reid GE, et al. Identification of DIABLO, a mammalian protein that promotes apoptosis by binding to and antagonizing IAP proteins. Cell 2000;102:43–53.PubMedGoogle Scholar
  183. 183.
    Wang K, Yin XM, Chao DT, Milliman CL, Korsmeyer SJ. BID: a novel BH3 domain-only death agonist. Genes Dev 1996;10:2859–69.PubMedGoogle Scholar
  184. 184.
    Webb JL, Ravikumar B, Rubinsztein DC. Microtubule disruption inhibits autophagosome-lysosome fusion: implications for studying the roles of aggresomes in polyglutamine diseases. Int J Biochem Cell Biol 2004;36:2541–50.PubMedGoogle Scholar
  185. 185.
    Wei MC, Lindsten T, Mootha VK, Weiler S, Gross A, Ashiya M, et al. tBID, a membrane-targeted death ligand, oligomerizes BAK to release cytochrome c. Genes Dev 2000;14:2060–71.PubMedGoogle Scholar
  186. 186.
    Weiss JN, Korge P, Honda HM, Ping P. Role of the mitochondrial permeability transition in myocardial disease. Circ Res 2003;93:292–301.PubMedGoogle Scholar
  187. 187.
    Werneburg N, Guicciardi ME, Yin XM, Gores GJ. TNF-alpha-mediated lysosomal permeabilization is FAN and caspase 8/Bid dependent. Am J Physiol Gasterointest Liver Physiol 2004;287:G436–43.Google Scholar
  188. 188.
    Winchester BG. Lysosomal membrane proteins. Eur J Paediatr Neurol 2001;5 Suppl A:11–9.PubMedGoogle Scholar
  189. 189.
    Wolter KG, Hsu YT, Smith CL, Nechushtan A, Xi XG, Youle RJ. Movement of Bax from the cytosol to mitochondria during apoptosis. J Cell Biol 1997;139:1281–92.PubMedGoogle Scholar
  190. 190.
    Xu C, Bailly-Maitre B, Reed JC. Endoplasmic reticulum stress: cell life and death decisions. J Clin Invest 2005;115:2656–64.PubMedGoogle Scholar
  191. 191.
    Xue L, Fletcher GC, Tolkovsky AM. Mitochondria are selectively eliminated from eukaryotic cells after blockade of caspases during apoptosis. Curr Biol 2001;11:361–5.PubMedGoogle Scholar
  192. 192.
    Yamaguchi S, Yamaoka M, Okuyama M, Nitoube J, Fukui A, Shirakabe M, et al. Elevated circulating levels and cardiac secretion of soluble Fas ligand in patients with congestive heart failure. Am J Cardiol 1999;83:1500–3, A8.PubMedGoogle Scholar
  193. 193.
    Yamamoto A, Cremona ML, Rothman JE. Autophagy-mediated clearance of huntingtin aggregates triggered by the insulin-signaling pathway. J Cell Biol 2006;172:719–31.PubMedGoogle Scholar
  194. 194.
    Yamamoto A, Tagawa Y, Yoshimori T, Moriyama Y, Masaki R, Tashiro Y. Bafilomycin A1 prevents maturation of autophagic vacuoles by inhibiting fusion between autophagosomes and lysosomes in rat hepatoma cell line, H-4-II-E cells. Cell Struct Funct 1998;23:33–42.PubMedCrossRefGoogle Scholar
  195. 195.
    Yan L, Vatner DE, Kim SJ, Ge H, Masurekar M, Massover WH, et al. Autophagy in chronically ischemic myocardium. Proc Natl Acad Sci USA 2005;102:13807–12.PubMedGoogle Scholar
  196. 196.
    Yasuda M, Theodorakis P, Subramanian T, Chinnadurai G. Adenovirus E1B-19K/BCL-2 interacting protein BNIP3 contains a BH3 domain and a mitochondrial targeting sequence. J Biol Chem 1998;273:12415–21.PubMedGoogle Scholar
  197. 197.
    Yu L, Alva A, Su H, Dutt P, Freundt E, Welsh S, et al. Regulation of an ATG7-beclin 1 program of autophagic cell death by caspase-8. Science 2004;304:1500–2.PubMedGoogle Scholar
  198. 198.
    Yu L, Wan F, Dutta S, Welsh S, Liu Z, Freundt E, et al. Autophagic programmed cell death by selective catalase degradation. Proc Natl Acad Sci USA 2006;103:4952–7.PubMedGoogle Scholar
  199. 199.
    Yuan H, Williams SD, Adachi S, Oltersdorf T, Gottlieb RA. Cytochrome c dissociation and release from mitochondria by truncated Bid and ceramide. Mitochondrion 2003;2:237–44.PubMedGoogle Scholar
  200. 200.
    Zeng X, Overmeyer JH, Maltese WA. Functional specificity of the mammalian Beclin-Vps34 PI 3-kinase complex in macroautophagy versus endocytosis and lysosomal enzyme trafficking. J Cell Sci 2006;119:259–70.PubMedGoogle Scholar
  201. 201.
    Zerial M, Mcbride H. Rab proteins as membrane organizers. Nat Rev Mol Cell Biol 2001;2:107–17.PubMedGoogle Scholar
  202. 202.
    Zha J, Weiler S, Oh KJ, Wei MC, Korsmeyer SJ. Posttranslational N-myristoylation of BID as a molecular switch for targeting mitochondria and apoptosis. Science 2000;290:1761–5.PubMedGoogle Scholar
  203. 203.
    Zhu HL, Stewart AS, Taylor MD, Vijayasarathy C, Gardner TJ, Sweeney HL. Blocking free radical production via adenoviral gene transfer decreases cardiac ischemia–reperfusion injury. Mol Ther 2000;2:470–5.PubMedGoogle Scholar
  204. 204.
    Zweier JL, Flaherty JT, Weisfeldt ML. Proc Natl Acad Sci USA 1987;84:1404–7.PubMedGoogle Scholar

Copyright information

© Springer Science + Business Media, LLC 2006

Authors and Affiliations

  • Anne Hamacher-Brady
    • 1
  • Nathan Ryan Brady
    • 1
  • Roberta Anne Gottlieb
    • 1
  1. 1.Department of Molecular and Experimental Medicine MEM-220The Scripps Research InstituteSan DiegoUSA

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