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Autophagy: Many paths to the same end

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Abstract

Different mechanisms lead to the degradation of intracellular proteins in the lysosomal compartment. Activation of one autophagic pathway or another, under specific cellular conditions, plays an important role in the ability of the cell to adapt to environmental changes. Each form of autophagy has its own individual characteristics, but it also shares common steps and components with the others. This interdependence of the autophagic pathways confers to the lysosomal system, both specificity and flexibility on substrate degradation. We describe in this review some of the recent findings on the molecular basis and regulation for each of the different autophagic pathways. We also discuss the cellular consequences of their interdependent function. Malfunctioning of the autophagic systems has dramatic consequences, especially in non-dividing differentiated cells. Using the heart as an example of such cells, we analyze the relevance of autophagy in aging and cell death, as well as in different pathological conditions. (Mol Cell Biochem 263: 55–72, 2004)

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References

  1. Kirschner M: Intracellular proteolysis. Trends Cell Biol 9: M42–M45, 1999

    Google Scholar 

  2. Squier TC: Oxidative stress and protein aggregation during biological aging. Exp Gerontol 36: 1539–1550, 2001

    Google Scholar 

  3. Kourie JI, Henry CL: Protein aggregation and deposition: implications for ion channel formation and membrane damage. Croat Med J 42: 359–374, 2001

    Google Scholar 

  4. Imai J, Yashiroda H, Maruya M, Yahara I, Tanaka K: Proteasomes and molecular chaperones: Cellular machinery responsible for folding and destruction of unfolded proteins. Cell Cycle 2: 585–590, 2003

    Google Scholar 

  5. Perrin BJ, Huttenlocher A: Calpain. Int J Biochem Cell Biol 34: 722–725, 2002

    Google Scholar 

  6. Cuervo AM, Dice JF: Lysosomes, a meeting point of proteins, chap-erones, and proteases. J Mol Med 76: 6–12, 1998

    Google Scholar 

  7. Dice JF: Lysosomal Pathways of Protein Degradation. Landes Bio-science, Austin, TX, 2000, pp 107

  8. Stennicke HR, Ryan CA, Salvesen GS: Retrieval from execution: The molecular basis of caspase inhibition. Trends Biochem Sci 27: 94–101, 2002

    Google Scholar 

  9. Kim J, Huang WP, Stromhaug PE, Klionsky DJ: Convergence of mul-tiple autophagy and cytoplasm to vacuole targeting components to a perivacuolar membrane compartment prior to de novo vesicle formation. J Biol Chem 277: 763–773, 2002

    Google Scholar 

  10. Wang CW, Klionsky DJ: The molecular mechanism of autophagy. Mol Med 9: 65–76, 2003

    Google Scholar 

  11. Seglen PO, Berg TO, Blankson H, Fengsrud M, Holen I, Stromhaug PE: Structural aspects of autophagy. Adv Exp Med Biol 389: 103–111, 1996

    Google Scholar 

  12. Mortimore GE, Miotto G, Venerando R, Kadowaki M: Autophagy. Subcell Biochem 27: 93–135, 1996

    Google Scholar 

  13. Thumm M: Structure and function of the yeast vacuole and its role in autophagy. Microsc Res Tech 51: 563–572, 2000

    Google Scholar 

  14. Ohsumi Y: Molecular dissection of autophagy: two ubiquitin-like sys-tems. Nat Rev Mol Cell Biol 2: 211–216, 2001

    Google Scholar 

  15. Tsukada M, Ohsumi M: Isolation and characterization of autophagy-defective mutants of Saccharomyces cerevisiae. FEBS Lett 333: 169–174, 1993

    Google Scholar 

  16. Thumm M: Isolation of autophagocytosis mutants of Saccharomyces cerevisiae. FEBS Lett 349: 275–280, 1994

    Google Scholar 

  17. Harding TM: Isolation and characterization of yeast mutants in the cytoplasm to vacuoles protein targeting pathway. J Cell Biol 131: 591–602, 1995

    Google Scholar 

  18. Klionsky D, Cregg J, Dunn WJ, Emr S, Sakai Y, Sandoval I, Sibirny A, Subramani S, Thumm M, Veenhuis M, Ohsumi Y: A unified nomenclature for yeast autophagy-related genes. Dev Cell: 539–545, 2003

  19. Hammond EM, Brunet CL, Johnson GD, Parkhill J, Milner AE, Brady G, Gregory CD, Grand RJ: Homology between a human apoptosis specific protein and the product of APG5, a gene involved in autophagy in yeast. FEBS Lett 425: 391–395, 1998

    Google Scholar 

  20. Mizushima N, Yamamoto A, Hatano M, Kobayashi Y, Kabeya Y, Suzuki K, Tokuhisa T, Ohsumi Y, Yoshimori T: Dissection of au-tophagosome formation using Apg5-deficient mouse embryonic stem cells. J Cell Biol 152: 657–668, 2001

    Google Scholar 

  21. Tanida I, Tanida-Miyake E, Ueno T, Kominami E: The human homolog of Saccharomyces cerevisiae Apg7p is a Protein-activating enzyme for multiple substrates including human Apg12p, GATE-16, GABARAP, and MAP-LC3. J Biol Chem 276: 1701–1706, 2001

    Google Scholar 

  22. Tanida I, Tanida-Miyake E, Komatsu M, Ueno T, Kominami E: Human Apg3p/Aut1p homologue is an authentic E2 enzyme for multiple substrates, GATE-16, GABARAP, and MAP-LC3, and facilitates the conjugation of hApg12p to hApg5p. J Biol Chem 277: 13739–13744, 2002

    Google Scholar 

  23. Marino G, Uria J, Puente X, Quesada V, Bordallo J, Lopez-Ortin C: Human autophagins, a family of cysteine proteinases potentially impli-cated in cell degradation by autophagy. J Biol Chem 278: 3671–3678, 2003

    Google Scholar 

  24. Doelling J, Walker J, Friedman E, Thompson A, Vierstra R: The APG8/12-activating enzyme APG7 is required for proper nutrient re-cycling and senescence is Arabidopsis thaliana. J Biol Chem 277: 33105–33114, 2002

    Google Scholar 

  25. Noda T, Suzuki K, Ohsumi Y: Yeast autophagosomes: de novo forma-tion of a membrane structure. Trends Cell Biol 12: 231–235, 2002

    Google Scholar 

  26. Suzuki K, Kirisako T, Kamada Y, Mizushima N, Noda T, Ohsumi Y: The pre-autophagosomal structure organized by concerted functions of APG genes is essential for autophagosome formation. EMBO J 20: 5971–5981, 2001

    Google Scholar 

  27. Seglen PO, Gordon PB, Holen I: Non-selective autophagy. Sem Cell Biol 1: 441–448, 1990

    Google Scholar 

  28. Mizushima N, Ohsumi Y, Yoshimori T: Autophagosome formation in mammalian cells. Cell Struct Funct 3: 815–824, 2002

    Google Scholar 

  29. Ichimura Y, Kirisako T, Takao T, Satomi Y, Shimonishi Y, Ishihara N, Mizushima N, Tanida I, Kominami E, Ohsumi M, Noda T, Ohsumi Y: A ubiquitin-like system mediates protein lipidation. Nature 408: 488–492, 2000

    Google Scholar 

  30. Kirisako T, Baba M, Ishihara N, Miyazawa K, Ohsumi M, Yoshimori T, Noda T, Ohsumi Y: Formation process of autophagosome is traced with Apg8/Aut7p in yeast. J Cell Biol 147: 435–446, 1999

    Google Scholar 

  31. Mizushima N, Yoshimori T, Ohsumi Y: Role of the Apg12 conjugation system in mammalian autophagy. Int J Biochem Cell Biol 35: 553–561, 2003

    Google Scholar 

  32. Mizushima N, Noda T, Yoshimori T, Tanaka Y, Ishii T, George MD, Klionsky DJ, Ohsumi M, Ohsumi Y: A protein conjugation system essential for autophagy. Nature 395: 395–398, 1998

    Google Scholar 

  33. Komatsu M, Tanida I, Ueno T, Ohsumi M, Ohsumi Y, Kominami E: The C-terminal region of an Apg7p/Cvt2p is required for homodimerization.69 and is essential for its E1 activity and E1-E2 complex formation. J Biol Chem 276: 9846–9854, 2001

    Google Scholar 

  34. Shintani T, Mizushima N, Ogawa Y, Matsuura A, Noda T, Ohsumi Y: Apg10p, a novel protein-conjugating enzyme essential for autophagy in yeast. EMBO J 18: 5234–5241, 1999

    Google Scholar 

  35. Kuma A, Mizushima N, Ishihara N, Ohsumi Y: Formation of the ap-proximately 350-kDa Apg12-Apg5.Apg16 multimeric complex, me-diated by Apg16 oligomerization, is essential for autophagy in yeast. J Biol Chem 277: 18619–18625, 2002

    Google Scholar 

  36. Kihara A, Noda T, Ishihara N, Ohsumi Y: Two distinct Vps34 phos-phatidylinositol 3-kinase complexes function in autophagy and car-boxypeptidase Y sorting in Saccharomyces cerevisiae.J Cell Biol 152: 519–530, 2001

    Google Scholar 

  37. Simonsen A, Wurmser AE, Emr SD, Stenmark H: The role of phospho-inositides in membrane transport. Curr Opin Cell Biol 13: 485–492, 2001

    Google Scholar 

  38. Matsuura A, Tsukada M, Wada Y, Ohsumi Y: Apg1p, a novel protein ki-nase required for the autophagic process in Saccharomyces cerevisiae. Gene 192: 245–250, 1997

    Google Scholar 

  39. Abeliovich H, Zhang C, Dunn WJ, Shokat K, Klionsky D: Chemical genetic analysis of Apg1 reveals a non-kinase role in the induction of autophagy. Mol Biol Cell 14: 477–490, 2003

    Google Scholar 

  40. Noda T, Kim J, Huang WP, Baba M, Tokunaga C, Ohsumi Y, Klionsky DJ: Apg9p/Cvt7p is an integral membrane protein required for trans-port vesicle formation in the Cvt and autophagy pathways. J Cell Biol 148: 465–480, 2000

    Google Scholar 

  41. Shintani T, Suzuki K, Kamada Y, Noda T, Ohsumi Y: Apg2p functions in autophagosome formation on the perivacuolar structure. J Biol Chem 276: 30452–30460, 2001

    Google Scholar 

  42. Ishihara N, Hamasaki M, Yokota S, Suzuki K, Kamada Y, Kihara A, Yoshimori T, Noda T, Ohsumi Y: Autophagosome requires specific early Sec proteins for its formation and NSF/SNARE for vacuolar fusion. Mol Biol Cell 12: 3690–3702, 2001

    Google Scholar 

  43. Darsow T, Rieder SE, Emr SD: Amultispecificity syntaxin homologue, Vam3p, essential for autophagic and biosynthetic protein transport to the vacuole. J Cell Biol 138: 517–529, 1997

    Google Scholar 

  44. Gaits F, Russell P: Vacuole fusion regulated by protein phosphatase 2C in fission yeast. Mol Biol Cell 10: 2647–2654, 1999

    Google Scholar 

  45. Munafo DB, Colombo MI: Induction of autophagy causes dramatic changes in the subcellular distribution of GFP-Rab24. Traffic 3: 472–482, 2002

    Google Scholar 

  46. Codogno P, Ogier-Denis E, Houri J: Signal transduction pathways in macroautophagy. Cell Signal 9: 125–130, 1997

    Google Scholar 

  47. Meijer A: Amino acids as regulators and components of nonproteino-genic pathways. J Nutr 133: 2057S–2062S, 2003

    Google Scholar 

  48. Ohshita T: Suppression of autophagy by ethionine administration in male rat liver in vivo. Toxicology 147: 51–57, 2000

    Google Scholar 

  49. Telbisz A, Kovacs AL: Intracellular protein degradation and autophagy in isolated pancreatic acini of the rat. Cell Biochem Func 18: 29–40, 2000

    Google Scholar 

  50. Holen I, Gordon PB, Seglen PO: Inhibition of hepatocytic autophagy by okadaic acid and other protein phosphatase inhibitors. Eur J Biochem 215: 113–122, 1993

    Google Scholar 

  51. Gordon PB, Holen I, Fosse M, Rotnes JS, Seglen PO: Dependence of hepatocytic autophagy on intracellularly sequestered calcium. J Biol Chem 268: 26107–26112, 1993

    Google Scholar 

  52. Kadowaki M, Venerando R, Miotto G, Mortimore GE: Mechanism of autophagy in permeabilized hepatocytes: Evidence for regula-tion by GTP binding proteins. Adv Exp Med Biol 389: 113–119, 1996

    Google Scholar 

  53. Petiot A, Ogier-Denis E, Bauvy C, Cluzeaud F, Vandewalle A, Codogno P: Subcellular localization of the Galphai3 protein and G alpha interacting protein, two proteins involved in the control of macroautophagy in human colon cancer HT-29 cells. Biochem J 337: 289–295, 1999

    Google Scholar 

  54. Blommaart EFC, Krause U, Schellens JPM, Vreeling-Sindelárová H, Meijer AJ: The phosphatidylinositol 3-kinase inhibitors wortmannin and LY294002 inhibit autophagy in isolated rat hepatocytes. Eur J Biochem 243: 240–246, 1997

    Google Scholar 

  55. Petiot A, Ogier-Denis E, Blommaart E, Meijer A, Codogno P: Distinct classes of phosphatidylinositol 3-kinases are involved in signaling pathways that control macroautophagy in HT-29 cells. J Biol Chem 275: 992–998, 2000

    Google Scholar 

  56. Noda T, Ohsumi Y: Tor, a phosphatidylinositol kinase homologue, controls autophagy in yeast. J Biol Chem 273: 3963–3966, 1998

    Google Scholar 

  57. Huang WP, Scott SV, Kim J, Klionsky DJ: The itinerary of a vesi-cle component, Aut7p/Cvt5p, terminates in the yeast vacuole via the autophagy/Cvt pathways. J Biol Chem 275: 5845–5851, 2000

    Google Scholar 

  58. Kamada Y, Funakoshi T, Shintani T, Nagano K, Ohsumi M, Ohsumi Y: Tor-mediated induction of autophagy via an Apg1 protein kinase complex. J Cell Biol 150: 1507–1513, 2000

    Google Scholar 

  59. Dennis PB, Jaeschke A, Saitoh M, Fowler B, S.C. K, Thomas G: Mam-malian TOR: A Homeostatic ATP Sensor. Science 294: 1102–1105, 2001

    Google Scholar 

  60. Mordier S, Deval C, Bechet D, Tassa A, Ferrara M: Leucine limitation induces autophagy and activation of lysosome-dependent proteoly-sis in C2C12 myotubes through a mammalian target of rapamycin-independent signaling pathway. J Biol Chem 275: 29900–29906, 2000

    Google Scholar 

  61. Thumm M, Kadowaki T: The loss of Drosophila APG4/AUT2 function modifies the phenotypes of cut and Notch signaling pathway mutants. Mol Genet Genomics 266: 657–663, 2001

    Google Scholar 

  62. Kovacs AL, Rez G, Palfia Z, Kovacs J: Autophagy in the epithelial cells of murine seminal vesicle in vitro. Formation of large sheets of nascent isolation membranes, sequestration of the nucleus and inhibition by wortmannin and 3-ethyladenine. Cell Tissue Res 302: 253–261, 2000

    Google Scholar 

  63. Sakai Y, Koller A, Rangell LK, Keller GA, Subramani S: Peroxisome degradation by microautophagy in Pichia pastoris: identification of specific steps and morphological intermediates. J Cell Biol 141: 625–636, 1998

    Google Scholar 

  64. Sattler T, Mayer A: Cell-free reconstitution of microautophagic vac-uole invagination and vesicle formation. J Cell Biol 151: 529–538, 2000

    Google Scholar 

  65. Marzella L, Ahlberg J, Glaumann H: Autophagy, heterophagy, mi-croautophagy and crinophagy as the means for intracellular degra-dation. Virchows Arch B Cell Pathol Incl Mol Pathol 36: 219–234, 1981

    Google Scholar 

  66. Ahlberg J, Marzella L, Glaumann H: Uptake and degradation of pro-teins by isolated rat liver lysosomes. Suggestion of a microautophagic pathway of proteolysis. Lab Invest 47: 523–532, 1982

    Google Scholar 

  67. Ahlberg J, Glaumann H: Uptake—microautophagy—and degrada-tion of exogenous proteins by isolated rat liver lysosomes. Effects of pH, ATP, and inhibitors of proteolysis. Exp Mol Pathol 42: 78–88, 1985

    Google Scholar 

  68. Muller O, Sattler T, Flotenmeyer M, Schwarz H, Plattner H, Mayer A: Autophagic tubes: vacuolar invaginations involved in lateral membrane sorting and inverse vesicle budding. J Cell Biol 151: 519–528, 2000

    Google Scholar 

  69. Mukaiyama H, Oku M, Baba M, Samizo T, Hammond AT, Glick BS, Kato N, Sakai Y: Paz2 and 13 other PAZ gene products regulate vacuolar engulfment of peroxisomes during micropexophagy. Genes Cells 7: 75–90, 2002

    Google Scholar 

  70. Mortimore GE, Lardeux BR, Adams CE: Regulation of microau-tophagy and basal protein turnover in rat liver. Effects of short-term starvation. J Biol Chem 263: 2506–2512, 1988

    Google Scholar 

  71. Veenhuis M, Salomons FA, Van Der Klei IJ: Peroxisome biogenesis and degradation in yeast: a structure/function analysis. Microsc Res Tech 51: 584–600, 2000.70

    Google Scholar 

  72. Auteri J, Okada A, Bochaki V, Dice J: Regulation of intracellular pro-tein degradation in IMR-90 human diploid fibroblasts. J Cell Physiol 115: 159–166, 1983

    Google Scholar 

  73. Dice JF: Peptide sequences that target cytosolic proteins for lysosomal proteolysis. Trends Biochem Sci 15: 305–309, 1990

    Google Scholar 

  74. Chiang H, Terlecky S, Plant C, Dice J: A role for a 70 kDa heat shock protein in lysosomal degradation of intracellular protein. Science 246: 382–385, 1989

    Google Scholar 

  75. Agarraberes FA, Dice JF: A molecular chaperone complex at the lyso-somal membrane is required for protein translocation. J Cell Sci 114: 2491–2499, 2001

    Google Scholar 

  76. Cuervo A, Dice J: A receptor for the selective uptake and degradation of proteins by lysosomes. Science 273: 501–503, 1996

    Google Scholar 

  77. Salvador N, Aguado C, Horst M, Knecht E: Import of a cytosolic protein into lysosomes by chaperone-mediated autophagy depends on its folding state. J Biol Chem 275: 27447–27456, 2000

    Google Scholar 

  78. Agarraberes F, Terlecky S, Dice J: An intralysosomal hsp70 is required for a selective pathway of lysosomal protein degradation. J Cell Biol 137: 825–834, 1997

    Google Scholar 

  79. Cuervo A, Dice J, Knecht E: A lysosomal population responsible for the hsc73-mediated degradation of cytosolic proteins in lysosomes. J Biol Chem 272: 5606–5615, 1997

    Google Scholar 

  80. Terlecky S, Dice J: Polypeptide import and degradation by isolated lysosomes. J Biol Chem 268: 23490–23495, 1993

    Google Scholar 

  81. Cuervo A, Hu W, Lim B, Dice J: IkB is a substrate for a selec-tive pathway of lysosomal proteolysis. Mol Biol Cell 9: 1995–2010, 1998

    Google Scholar 

  82. Cuervo A, Hildebrand H, Bomhard E, Dice J: Direct lysosomal uptake of alpha2-microglobulin contributes to chemically induced nephropa-thy. Kidney Int 55: 529–545, 1999

    Google Scholar 

  83. Fuertes G, Martin De Llano J, Villarroya A, Rivett A, Knecht E: Changes in the proteolytic activities of proteasomes and lysosomes in human fibroblasts produced by serum withdrawal, amino-acid de-privation and confluent conditions. Biochem J 375: 75–86, 2003

    Google Scholar 

  84. Wing S, Chiang HL, Goldberg AL, Dice JF:Proteins containing peptide sequences related to KFERQ are selectively depleted in liver and heart, but not skeletal muscle, of fasted rats. Biochem J 275: 165–169, 1991

    Google Scholar 

  85. Martin A, Joseph J, Cuervo A: Stimulatory effect of vitamin C on autophagy in glial cells. J Neurochem 82: 538–549, 2002

    Google Scholar 

  86. Franch HA, Sooparb S, Du J, Brown NS: A mechanism regulating proteolysis of specific proteins during renal tubular cell growth. J Biol Chem 276: 19126–19131, 2001

    Google Scholar 

  87. Cuervo AM, Dice JF: Unique properties of lamp2a compared to other lamp2 isoforms. J Cell Sci 113: 4441–4450, 2000

    Google Scholar 

  88. Cuervo AM, Dice JF: Regulation of lamp2a levels in the lysosomal membrane. Traffic 1: 570–583, 2000

    Google Scholar 

  89. Cuervo AM, Mann L, Bonten E, d'Azzo A, Dice J: Cathepsin A reg-ulates chaperone-mediated autophagy through cleavage of the lysoso-mal receptor. EMBO J 22: 12–19, 2003

    Google Scholar 

  90. Chiang HL, Schekman R, Hamamoto S: Selective uptake of cytosolic, peroxisomal, and plasma membrane proteins into the yeast lysosome for degradation. J Biol Chem 271: 9934–9941, 1996

    Google Scholar 

  91. Huang PH, Chiang HL: Identification of novel vesicles in the cytosol to vacuole protein degradation pathway. J Cell Biol 136: 803–810, 1997

    Google Scholar 

  92. Shieh HL, Chiang HL: In vitro reconstitution of glucose-induced tar-geting of fructose-1, 6-bisphosphatase into the vacuole in semi-intact yeast cells. J Biol Chem 273: 3381–3387, 1998

    Google Scholar 

  93. Brown CR, McCann JA, Chiang HL: The heat shock protein Ssa2p is required for import of fructose-1, 6-bisphosphatase into Vid vesicles. J Cell Biol 150: 65–76, 2000

    Google Scholar 

  94. Brown CR, Cui DY, Hung GG, Chiang HL: Cyclophilin A mediates Vid22p function in the import of fructose-1,6-bisphosphatase into Vid vesicles. J Biol Chem 276: 48017–48026, 2001

    Google Scholar 

  95. Chiang MC, Chiang HL: Vid24p, a novel protein localized to the fructose-1, 6-bisphosphatase-containing vesicles, regulates targeting of fructose-1,6-bisphosphatase from the vesicles to the vacuole for degradation. J Cell Biol 140: 1347–1356, 1998

    Google Scholar 

  96. Hoffman M, Chiang HL: Isolation of degradation-deficient mutants de-fective in the targeting of fructose-1,6-bisphosphatase into the vacuole for degradation in Saccharomyces cerevisiae. Genetics 143: 1555–1566, 1996

    Google Scholar 

  97. Shieh HL, Chen Y, Brown CR, Chiang HL: Biochemical analysis of fructose-1,6-bisphosphatase import into vacuole import and degradation vesicles reveals a role for UBC1 in vesicle biogenesis. J Biol Chem 276: 10398–10406, 2001

    Google Scholar 

  98. Brown CR, Liu J, Hung GC, Carter D, Cui D, Chiang HL: The Vid vesicle to vacuole trafficking event requires components of the SNARE membrane fusion machinery. J Biol Chem 278: 25688–25699, 2003

    Google Scholar 

  99. Stromhaug PE, Berg TO, Fengsrud M, Seglen PO: Purification and characterization of autophagosomes from rat hepatocytes. Biochem J 335: 217–224, 1998

    Google Scholar 

  100. Ogier-Denis E, Bauvy C, Cluzeaud F, Vandewalle A, Codogno P: Glucose persistence on high-mannose oligosaccharides selectively in-hibits the macroautophagic sequestration of N-linked glycoproteins. Biochem J 345: 459–466, 2000

    Google Scholar 

  101. Lenk SE, Susan PP, Hickson I, Jasionowski T, Dunn WA, Jr.: Ubiq-uitinated aldolase B accumulates during starvation-induced lysosomal proteolysis. J Cell Physiol 178: 17–27, 1999

    Google Scholar 

  102. Masaki R, Yamamoto A, Tashiro Y: Cytochrome P-450 and NADPH-cytochrome P450 reductase are degraded in the autolysoosmes in rat liver. J Cell Biol 104: 1207–1215, 1987

    Google Scholar 

  103. Roberts P, Moshitch-Moshkovitz S, Kvam E, O'Toole E, Winey M, Goldfarb D: Piecemeal microautophagy of nucleus in Saccharomyces cerevisiae. Mol Biol Cell 14: 129–141, 2003

    Google Scholar 

  104. Bellu A, Kiel J: Selective degradation of peroxisomes in yeasts. Microsc Res Tech 61: 161–170, 2003

    Google Scholar 

  105. Locci Cubeddu T, Masiello P, Pollera M, Bergamini E: Effects of an-tilipolytic agents on rat liver peroxisomes and peroxisomal oxidative activities. Biochim Biophys Acta 839: 96–104, 1985

    Google Scholar 

  106. Nardacci R, Sartori C, Stefanini S: Selective autophagy of clofibrate-induced rat liver peroxisomes. Cytochemistry and immunocytochemistry on tissue specimens and on fractions obtained by Nycodenz den-sity gradient centrifugation. Cell Mol Biol 46: 1277–1290, 2000

    Google Scholar 

  107. Tuttle DL, Lewin AS, Dunn WA, Jr.: Selective autophagy of per-oxisomes in methylotrophic yeasts. Eur J Cell Biol 60: 283–290, 1993

    Google Scholar 

  108. Yuan W, Stromhaug PE, Dunn WA, Jr.: Glucose-induced autophagy of peroxisomes in Pichia pastoris requires a unique E1-like protein. Mol Biol Cell 10: 1353–1366, 1999

    Google Scholar 

  109. Bellu AR, Kram A, Kiel JA, Veenhuis M, van der Klei IJ: Glucose-induced and nitrogen-starvation-induced peroxisome degradation are distinct processes in Hansenula polymorpha that involve both common and unique genes. FEM Yeast Res 1: 23–31, 2002

    Google Scholar 

  110. Hutchins MU, Veenhuis M, Klionsky DJ: Peroxisome degrada-tion in Saccharomyces cerevisiae is dependent on machinery of macroautophagy and the Cvt pathway. J Cell Sci 112: 4079–4087, 1999

    Google Scholar 

  111. Bellu A, Komori M, van der Klei I, Kiel J, Veenhuis M: Peroxisome biogenesis and selective degradation converge at Pex14p. J Biol Chem 276: 44570–44574, 2001

    Google Scholar 

  112. Subramani S, Koller A, Snyder WB: Import of peroxisomal matrix and membrane proteins. Ann Rev Biochem 69: 399–418, 2000

    Google Scholar 

  113. Xue L, Fletcher GC, Tolkovsky AM: Mitochondria are selectively eliminated from eukaryotic cells after blockade of caspases during apoptosis. Curr Biol 11: 361–365, 2001.71

    Google Scholar 

  114. Tolkovsky AM, Xue L, Fletcher G, Borutaite V: Mitochondrial disappearance from cells: a clue to the role of autophagy in programmed cell death and disease? Biochimie 84: 233–240, 2002

    Google Scholar 

  115. Takano-Ohmuro H, Mukaida M, Kominami E, Morioka K: Autophagy in embryonic erythroid cells: its role in maturation. Eur J Cell Biol 79: 759–764, 2000

    Google Scholar 

  116. Elmore SP, Qian T, Grissom SF, Lemasters JJ: The mitochondrial per-meability transition initiates autophagy in rat hepatocytes. FASEB J 15: 2286–2287, 2001

    Google Scholar 

  117. Lemasters JJ, Quian T, He L, Kim J, Elmore S, Cascio W, Brenner D: Role of mitochondrial inner membrane permeabilization in necrotic cell death, apoptosis, and autophagy. Antioxid Redox Signal 4: 769–781, 2002

    Google Scholar 

  118. Brunk U, Terman A: The mitochondrial-lysosomal axis theory of aging: accumulation of damaged mitochondria as a result of imperfect autophagocytosis. Eur J Biochem 268: 1996–2002, 2002

    Google Scholar 

  119. Suriapranata I, Epple UD, Bernreuther D, Bredschneider M, Sovarasteanu K, Thumm M: The breakdown of autophagic vesicles inside the vacuole depends on Aut4p. J Cell Sci 113: 4025–4033, 2000

    Google Scholar 

  120. Katunuma N, Kominami E: Structures and functions of lysosomal thiol proteinases and their endogenous inhibitor. Curr Top Cell Regul 22: 71–101, 1983

    Google Scholar 

  121. Barrett AJ, Kirschke H: Cathepsin B, Cathepsin H, and cathepsin L. Meth Enzymol 80: 535–561, 1981

    Google Scholar 

  122. Arunachalam B, Phan UT, Geuze HJ, Cresswell P: Enzymatic reduc-tion of disulfide bonds in lysosomes: characterization of a gamma-interferon-inducible lysosomal thiol reductase (GILT). Proc Natl Acad Sci 97: 745–750, 2000

    Google Scholar 

  123. Reed CH: Diagnostic applications of cystatin C. Br J Biomed Sci 57: 323–329, 2000

    Google Scholar 

  124. Jadot M, Dubois F, Wattiaux-De Coninck S, Wattiaux R: Supramolec-ular assemblies from lysosomal matrix proteins and complex lipids. Eur J Biochem 249: 862–869, 1997

    Google Scholar 

  125. Epple UD, Suriapranata I, Eskelinen EL, Thumm M: Aut5/Cvt17p, a putative lipase essential for disintegration of autophagic bodies inside the vacuole. J Bacteriol 183: 5942–5955, 2001

    Google Scholar 

  126. Teter SA, Eggerton KP, Scott SV, Kim J, Fischer AM, Klionsky DJ: Degradation of lipid vesicles in the yeast vacuole requires function of Cvt17, a putative lipase. J Biol Chem 276: 2083–2087, 2001

    Google Scholar 

  127. Thamotharan M, Lombardo YB, SZ, Adibi S: An active mechanism for completion of the final stage of protein degradation in the liver, lysosoml transport of dipeptides. J Biol Chem 272: 11786–11790, 1997

    Google Scholar 

  128. Klionsky DJ, Emr SD: Autophagy as a regulated pathway of cellular degradation. Science 290: 1717–1721, 2000

    Google Scholar 

  129. van Kerkhof P, Alves dos Santos C, Sachse M, Klumperman J, Bu G, Strous G: Proteasome inhibitors block a late step in lysosomal transport of selected membrane but not soluble proteins. Mol Biol Cell 12: 2556–2566, 2001

    Google Scholar 

  130. Liou W, Geuze HJ, Geelen MJ, Slot JW: The autophagic and endocytic pathways converge at the nascent autophagic vacuoles. J Cell Biol 136: 61–70, 1997

    Google Scholar 

  131. Stefanis L, Larsen K, Rideout H, Sulzer D, Greene L: Expression of A53T mutant but not wild-type alpha-synuclein in PC12 cells in-duces alterations of the ubiquitin-dependent degradation system, loss of dopamine release, and autophagic cell death. J Neurosci 21: 9549–9560, 2001

    Google Scholar 

  132. Hutchins MU, Klionsky DJ: Vacuolar localization of oligomeric alpha-mannosidase requires the cytoplasm to vacuole targeting and au-tophagy pathway components in Saccharomyces cerevisiae. J Biol Chem 276: 20491–20498, 2001

    Google Scholar 

  133. Scott SV, Nice DC, 3rd, Nau JJ, Weisman LS, Kamada Y, Keizer-Gunnink I, Funakoshi T, Veenhuis M, Ohsumi Y, Klionsky DJ: Apg13p and Vac8p are part of a complex of phosphoproteins that are required for cytoplasm to vacuole targeting. J Biol Chem 275: 25840–25849, 2000

    Google Scholar 

  134. Gevers W: Protein metabolism of the heart. J Mol Cell Cardiol 16: 3–32, 1984

    Google Scholar 

  135. Wing SS, Chiang HL, Goldberg AL, Dice JF: Proteins containing pep-tide sequences related to KFERQ are selectively depleted in liver and heart, but not skeletal muscle, of fasted rats. Biochem J 275: 165–169, 1991

    Google Scholar 

  136. Ward WF: The relentless effects of the aging process on protein turnover. Biogerontology 1: 195–199, 2000

    Google Scholar 

  137. Goto S, Takahashi R, Kumiyama AA, Radak Z, Hayashi T, Takenouchi M, Abe R: Implications of protein degradation in aging. Ann N Y Acad Sci 928: 54–64, 2001

    Google Scholar 

  138. Terman A: The effect of age on formation and elimination of au-tophagic vacuoles in mouse hepatocytes. Gerontology 41: 319–325, 1995

    Google Scholar 

  139. Cuervo AM, Dice JF: Age-related decline in chaperone-mediated au-tophagy. J Biol Chem 275: 31505–31513, 2000

    Google Scholar 

  140. Donati A, Cavallini G, Paradiso C, Vittorini S, Pollera M, Gori Z, Bergamini E: Age-related changes in the autophagic proteolysis of rat isolated liver cells: effects of antiaging dietary restrictions. J Gerontol 56: B375–383, 2001

    Google Scholar 

  141. Hariri M, Millane G, Guimond MP, Guay G, Dennis JW, Nabi IR: Biogenesis of multilamellar bodies via autophagy. Mol Biol Cell 11: 255–268, 2000

    Google Scholar 

  142. Dice J: Altered degradation of proteins microinjected into senescent human fibroblasts. J Biol Chem 257: 14624–14627, 1982

    Google Scholar 

  143. Terman A, Brunk U: Lipofuscin-Mechanisms of formation and increase with age. APMIS 106: 265–276, 1998

    Google Scholar 

  144. Lockwood TD: Redox control of protein degradation. Antioxid Redox Signal 2: 851–878, 2000

    Google Scholar 

  145. Takahashi M, Hoshii Y, Kawano H, Gondo T, Yokota T, Okabayashi H, Shimada I, Ishihara T: Ultrastructural evidence for the formation of amyloid fibrils within cardiomyocytes in isolated atrial amyloid. Amyloid 5: 35–42, 1998

    Google Scholar 

  146. Vittorini S, Paradiso C, Donati A, Cavallini G, Masini M, Gori Z, Pollera M, Bergamini E: The age-related accumulation of protein car-bonyl in rat liver correlates with the age-related decline in liver prote-olytic activities. J Gerontol 54: B318–323, 1999

    Google Scholar 

  147. Bednarski E, Lynch G: Selective suppression of cathepsin L results from elevations in lysosomal pH and is followed by proteolysis of tau protein. Neuroreport 9: 2089–2094, 1998

    Google Scholar 

  148. Melendez A, Talloczy Z, Scaman M, Eskelinen EL, Hall DH, Levine B: Essential role of autophagy genes in dauer development and lifespan extension in C. elegans. Science 301: 1387–1391, 2003

    Google Scholar 

  149. Bromme HJ, Holtz J: Apoptosis in the heart: when and why? Mol Cell Biochem 163–164: 261–275, 1996

    Google Scholar 

  150. Ollinger K: Inhibition of cathepsin D prevents free-radical-induced apoptosis in rat cardiomyocytes. Arch Biochem Biophys 373: 346–351, 2000

    Google Scholar 

  151. Brunk UT, Svensson I: Oxidative stress, growth factor starvation and Fas activation may all cause apoptosis through lysosomal leak. Redox Rep 4: 3–11, 1999

    Google Scholar 

  152. Shibata M, Kanamori S, Isahara K, Ohsawa Y, Konishi A, Kametaka S, Watanabe T, Ebisu S, Ishido K, Kominami E, Uchiyama Y: Participation of cathepsins B and D in apoptosis of PC12 cells following serum deprivation. Biochem Biophys Res Comm 251: 199–203, 1998

    Google Scholar 

  153. Roberg K, Kagedal K, Ollinger K: Microinjection of cathepsin d in-duces caspase-dependent apoptosis in fibroblasts. Am J Pathol 161: 89–96, 2002

    Google Scholar 

  154. Bursch W, Ellinger A, Gerner C, Frohwein U, Schulte-Hermann R: Programmed cell death (PCD). Apoptosis, autophagic PCD, or others? Ann N Y Acad Sci 926: 1–12, 2000.

    Google Scholar 

  155. Monney L, Olivier R, Otter I, Jansen B, Poirier GG, Borner C: Role of an acidic compartment in tumor-necrosis-factor-alpha-induced pro-duction of ceramide, activation of caspase-3 and apoptosis. Eur J Biochem 251: 295–303, 1998

    Google Scholar 

  156. Kostin S, Pool L, Elsasser A, Hein S, Drexler H, Arnon E, Hayakawa Y, Zimmermann R, Bauer E, Klovekorn W, Schaper J: Myocytes die by multiple mechanisms in failing human hearts. Circ Res 92: 715–724, 2003

    Google Scholar 

  157. Uchiyama Y: Autophagic cell death and its execution by lysosomal cathepsins. Arch Histol Cytol 64: 233–246, 2001

    Google Scholar 

  158. Thummel CS: Steroid-triggered death by autophagy. Bioessays 23: 677–682, 2001

    Google Scholar 

  159. Gorski S, Chittaranjar S, Pleasance E, Freeman J, Anderson C, Varhol R, Coughlin S, Zuyderduyn S, Jones S, Marra M: A SAGE approach to discovery of genes involved in autophagic cell death. Curr Biol 13: 358–363, 2003

    Google Scholar 

  160. Inbal B, Bialik S, Sabanay I, Shani G, Kimchi A: DAP kinase and DRP-1 mediate membrane blebbing and the formation of autophagic vesicles during programmed cell death. J Cell Biol 157: 455–468, 2002

    Google Scholar 

  161. Winchester B, Vellodi A, Young E: The molecular basis of lysosomal storage diseases and their treatment. Biochem Soc Trans 28: 150–154, 2000

    Google Scholar 

  162. Saftig P, Tanaka Y, Lullmann-Rauch R, von Figura K: Disease model: LAMP-2 enlightens Danon disease. Trends Mol Med 7: 37–39, 2001

    Google Scholar 

  163. Tanaka Y, Guhde G, Suter A, Eskelinen EL, Hartmann D, Lullmann-Rauch R, Janssen PM, Blanz J, von Figura K, Saftig P: Accumulation of autophagic vacuoles and cardiomyopathy in LAMP-2-deficient mice. Nature 406: 902–906, 2000

    Google Scholar 

  164. Sugie K, Yamamoto A, Murayama K, Oh S, Takahashi M, Mora M, Riggs J, Colomer J, Iturriaga C, Meloni A, Lamperti C, Saitoh S, Byrne E, DiMauro S, Nonaka I, Hirano M, Nishino I: Clinicopathological features of genetically confirmed Danon disease. Neurology 58: 1773–1778, 2002

    Google Scholar 

  165. Konecki D, Foetisch K, Zimmer K, Schlotter M, Lichter-Konecki U: An alternatively spliced form of the human lysosome-associated mem-brane protein-2 gene is expressed in a tissue-specific manner. Biochem Biophys Res Comm 215: 757–767, 1995

    Google Scholar 

  166. Suzuki T, Nakagawa M, Yoshikawa A, Sasagawa N, Yoshimori T, Ohsumi Y, Nishino I, Ishiura S, Nonaka I: The first molecular evi-dence that autophagy relates rimmed vacuole formation in chloroquine myopathy. J Biochem 131: 647–651, 2002

    Google Scholar 

  167. Terman A, Dalen H, Eaton JW, Neuzil J, Brunk UT: Mitochondrial recycling and aging of cardiac myocytes: the role of autophagocytosis. Exp Gerontol 38: 863–876, 2003

    Google Scholar 

  168. Nepomnyashchikh LM, Lushnikova EL, Semenov DE: Focal degrada-tion of cytoplasmic organelles in cardiomyocytes during regenerative and plastic myocardial insufficiency. Bull Exp Biol Med 130: 1190–1195, 2000

    Google Scholar 

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  1. Department of Anatomy and Structural Biology, Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, NY, USA

    Ana Maria Cuervo

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Cuervo, A.M. Autophagy: Many paths to the same end. Mol Cell Biochem 263, 55–72 (2004). https://doi.org/10.1023/B:MCBI.0000041848.57020.57

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