Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Timeline
  • Published:

Autophagy: from phenomenology to molecular understanding in less than a decade

Abstract

In 2000, it was suggested to me that “Autophagy will be the wave of the future; it will become the new apoptosis.” Few people would have agreed at the time, but this statement turned out to be prophetic, and this process of 'self-eating' rapidly exploded as a research field, as scientists discovered connections to cancer, neurodegeneration and even lifespan extension. Amazingly, the molecular breakthroughs in autophagy have taken place during only the past decade.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1: A dramatic increase in autophagy research.
Figure 2: Autophagy visualized by freeze-fracture electron microscopy.

References

  1. de Duve, C., Pressman, B. C., Gianetto, R., Wattiaux, R. & Appelmans, F. Tissue fractionation studies. 6. Intracellular distribution patterns of enzymes in rat-liver tissue. Biochem. J. 60, 604–617 (1955).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Ashford, T. P. & Porter, K. R. Cytoplasmic components in hepatic cell lysosomes. J. Cell Biol. 12, 198–202 (1962).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Clark, S. L. Jr. Cellular differentiation in the kidneys of newborn mice studied with the electron microscope. J. Biophys. Biochem. Cytol. 3, 349–362 (1957).

    PubMed  PubMed Central  Google Scholar 

  4. de Duve, C. & Wattiaux, R. Functions of lysosomes. Annu. Rev. Physiol. 28, 435–492 (1966).

    CAS  PubMed  Google Scholar 

  5. Novikoff, A. B. The proximal tubule cell in experimental hydronephrosis. J. Biophys. Biochem. Cytol. 6, 136–138 (1959).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Kopitz, J., Kisen, G. O., Gordon, P. B., Bohley, P. & Seglen, P. O. Nonselective autophagy of cytosolic enzymes by isolated rat hepatocytes. J. Cell Biol. 111, 941–953 (1990).

    CAS  PubMed  Google Scholar 

  7. Fengsrud, M., Lunde Sneve, M., Øverbye, A. & Seglen, P. O. in Autophagy (ed. Klionsky, D. J.) 11–25 (Landes Bioscience, Texas, 2004).

    Google Scholar 

  8. Seglen, P. O. in Lysosomes: Their Role in Protein Breakdown (eds Glaumann, H. & Ballard, F. J.) 371–414 (Academic Press, Florida, 1987).

    Google Scholar 

  9. Gordon, P. B. & Seglen, P. O. Prelysosomal convergence of autophagic and endocytic pathways. Biochem. Biophys. Res. Commun. 151, 40–47 (1988).

    CAS  PubMed  Google Scholar 

  10. Mizushima, N. et al. Dissection of autophagosome formation using Apg5-deficient mouse embryonic stem cells. J. Cell Biol. 152, 657–668 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Takeshige, K., Baba, M., Tsuboi, S., Noda, T. & Ohsumi, Y. Autophagy in yeast demonstrated with proteinase-deficient mutants and conditions for its induction. J. Cell Biol. 119, 301–311 (1992).

    CAS  PubMed  Google Scholar 

  12. Kim, J., Huang, W. -P., Stromhaug, P. E. & Klionsky, D. J. Convergence of multiple 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).

    CAS  PubMed  Google Scholar 

  13. Suzuki, K. et al. The pre-autophagosomal structure organized by concerted functions of APG genes is essential for autophagosome formation. EMBO J. 20, 5971–5981 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Deter, R. L., Baudhuin, P. & de Duve, C. Participation of lysosomes in cellular autophagy induced in rat liver by glucagon. J. Cell Biol. 35, C11–C16 (1967).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Pfeifer, U. Inhibition by insulin of the physiological autophagic breakdown of cell organelles. Acta Biol. Med. Ger. 36, 1691–1694 (1977).

    CAS  PubMed  Google Scholar 

  16. Mortimore, G. E. & Schworer, C. M. Induction of autophagy by amino-acid deprivation in perfused rat liver. Nature 270, 174–176 (1977).

    CAS  PubMed  Google Scholar 

  17. Seglen, P. O. & Gordon, P. B. 3-methyladenine: specific inhibitor of autophagic/lysosomal protein degradation in isolated rat hepatocytes. Proc. Natl Acad. Sci. USA 79, 1889–1892 (1982).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Holen, I., Gordon, P. B. & Seglen, P. O. Protein kinase-dependent effects of okadaic acid on hepatocytic autophagy and cytoskeletal integrity. Biochem. J. 284, 633–636 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Kunz, J. et al. Target of rapamycin in yeast, TOR2, is an essential phosphatidylinositol kinase homolog required for G1 progression. Cell 73, 585–596 (1993).

    CAS  PubMed  Google Scholar 

  20. Blommaart, E. F., Luiken, J. J., Blommaart, P. J., van Woerkom, G. M. & Meijer, A. J. Phosphorylation of ribosomal protein S6 is inhibitory for autophagy in isolated rat hepatocytes. J. Biol. Chem. 270, 2320–2326 (1995).

    CAS  PubMed  Google Scholar 

  21. Blommaart, E. F., Krause, U., Schellens, J. P., Vreeling-Sindelarova, H. & Meijer, A. J. The phosphatidylinositol 3-kinase inhibitors wortmannin and LY294002 inhibit autophagy in isolated rat hepatocytes. Eur. J. Biochem. 243, 240–246 (1997).

    CAS  PubMed  Google Scholar 

  22. Petiot, A., Ogier-Denis, E., Blommaart, E. F., Meijer, A. J. & 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).

    CAS  PubMed  Google Scholar 

  23. Arico, S. et al. The tumor suppressor PTEN positively regulates macroautophagy by inhibiting the phosphatidylinositol 3-kinase/protein kinase B pathway. J. Biol. Chem. 276, 35243–35246 (2001).

    CAS  PubMed  Google Scholar 

  24. Noda, T. & Ohsumi, Y. Tor, a phosphatidylinositol kinase homologue, controls autophagy in yeast. J. Biol. Chem. 273, 3963–3966 (1998).

    CAS  PubMed  Google Scholar 

  25. Bolender, R. P. & Weibel, E. R. A morphometric study of the removal of phenobarbital-induced membranes from hepatocytes after cessation of treatment. J. Cell Biol. 56, 746–761 (1973).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Beaulaton, J. & Lockshin, R. A. Ultrastructural study of the normal degeneration of the intersegmental muscles of Anthereae polyphemus and Manduca sexta (Insecta, Lepidoptera) with particular reference of cellular autophagy. J. Morphol. 154, 39–57 (1977).

    CAS  PubMed  Google Scholar 

  27. Veenhuis, M., Douma, A., Harder, W. & Osumi, M. Degradation and turnover of peroxisomes in the yeast Hansenula polymorpha induced by selective inactivation of peroxisomal enzymes. Arch. Microbiol. 134, 193–203 (1983).

    CAS  PubMed  Google Scholar 

  28. Lemasters, J. J. et al. The mitochondrial permeability transition in cell death: a common mechanism in necrosis, apoptosis and autophagy. Biochim. Biophys. Acta 1366, 177–196 (1998).

    CAS  PubMed  Google Scholar 

  29. Elmore, S. P., Qian, T., Grissom, S. F. & Lemasters, J. J. The mitochondrial permeability transition initiates autophagy in rat hepatocytes. FASEB J. 15, 2286–2287 (2001).

    CAS  PubMed  Google Scholar 

  30. Xue, L., Fletcher, G. C. & Tolkovsky, A. M. Mitochondria are selectively eliminated from eukaryotic cells after blockade of caspases during apoptosis. Curr. Biol. 11, 361–365 (2001).

    CAS  PubMed  Google Scholar 

  31. Harding, T. M., Morano, K. A., Scott, S. V. & Klionsky, D. J. Isolation and characterization of yeast mutants in the cytoplasm to vacuole protein targeting pathway. J. Cell Biol. 131, 591–602 (1995).

    CAS  PubMed  Google Scholar 

  32. Baba, M., Osumi, M., Scott, S. V., Klionsky, D. J. & Ohsumi, Y. Two distinct pathways for targeting proteins from the cytoplasm to the vacuole/lysosome. J. Cell Biol. 139, 1687–1695 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Harding, T. M., Hefner-Gravink, A., Thumm, M. & Klionsky, D. J. Genetic and phenotypic overlap between autophagy and the cytoplasm to vacuole protein targeting pathway. J. Biol. Chem. 271, 17621–17624 (1996).

    CAS  PubMed  Google Scholar 

  34. Scott, S. V., Baba, M., Ohsumi, Y. & Klionsky, D. J. Aminopeptidase I is targeted to the vacuole by a nonclassical vesicular mechanism. J. Cell Biol. 138, 37–44 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Scott, S. V. et al. Cytoplasm-to-vacuole targeting and autophagy employ the same machinery to deliver proteins to the yeast vacuole. Proc. Natl Acad. Sci. USA 93, 12304–12308 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Hutchins, M. U. & Klionsky, D. J. Vacuolar localization of oligomeric α-mannosidase requires the cytoplasm to vacuole targeting and autophagy pathway components in Saccharomyces cerevisiae. J. Biol. Chem. 276, 20491–20498 (2001).

    CAS  PubMed  Google Scholar 

  37. Klionsky, D. J., Cueva, R. & Yaver, D. S. Aminopeptidase I of Saccharomyces cerevisiae is localized to the vacuole independent of the secretory pathway. J. Cell Biol. 119, 287–299 (1992).

    CAS  PubMed  Google Scholar 

  38. Tsukada, M. & Ohsumi, Y. Isolation and characterization of autophagy-defective mutants of Saccharomyces cerevisiae. FEBS Lett. 333, 169–174 (1993).

    CAS  PubMed  Google Scholar 

  39. Klionsky, D. J. et al. A unified nomenclature for yeast autophagy-related genes. Dev. Cell 5, 539–545 (2003).

    CAS  PubMed  Google Scholar 

  40. Matsuura, A., Tsukada, M., Wada, Y. & Ohsumi, Y. Apg1p, a novel protein kinase required for the autophagic process in Saccharomyces cerevisiae. Gene 192, 245–250 (1997).

    CAS  PubMed  Google Scholar 

  41. Kabeya, Y., Kawamata, T., Suzuki, K. & Ohsumi, Y. Cis1/Atg31 is required for autophagosome formation in Saccharomyces cerevisiae. Biochem. Biophys. Res. Commun. 356, 405–410 (2007).

    CAS  PubMed  Google Scholar 

  42. Hutchins, M. U., Veenhuis, M. & Klionsky, D. J. Peroxisome degradation in Saccharomyces cerevisiae is dependent on machinery of macroautophagy and the Cvt pathway. J. Cell Sci. 112, 4079–4087 (1999).

    CAS  PubMed  Google Scholar 

  43. Zhang, Y. et al. The role of autophagy in mitochondria maintenance: characterization of mitochondrial functions in autophagy-deficient S. cerevisiae strains. Autophagy 3, 337–346 (2007).

    CAS  PubMed  Google Scholar 

  44. Klionsky, D. J. The molecular machinery of autophagy: unanswered questions. J. Cell Sci. 118, 7–18 (2005).

    CAS  PubMed  Google Scholar 

  45. Klionsky, D. J., Cuervo, A. M. & Seglen, P. O. Methods for monitoring autophagy from yeast to human. Autophagy 3, 181–206 (2007).

    CAS  PubMed  Google Scholar 

  46. Ohsumi, Y. Molecular dissection of autophagy: two ubiquitin-like systems. Nature Rev. Mol. Cell Biol. 2, 211–216 (2001).

    CAS  Google Scholar 

  47. 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. 273, 33889–33892 (1998).

    CAS  PubMed  Google Scholar 

  48. Kabeya, Y. et al. LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing. EMBO J. 19, 5720–5728 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Liang, X. H. et al. Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature 402, 672–676 (1999).

    CAS  PubMed  Google Scholar 

  50. Qu, X. et al. Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. J. Clin. Invest. 112, 1809–1820 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Yue, Z., Jin, S., Yang, C., Levine, A. J. & Heintz, N. Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor. Proc. Natl Acad. Sci. USA 100, 15077–15082 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Pattingre, S. et al. Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy. Cell 122, 927–939 (2005).

    CAS  PubMed  Google Scholar 

  53. Mathew, R. et al. Autophagy suppresses tumor progression by limiting chromosomal instability. Genes Dev. 21, 1367–1381 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Rikihisa, Y. Glycogen autophagosomes in polymorphonuclear leukocytes induced by Rickettsiae. Anat. Rec. 208, 319–327 (1984).

    CAS  PubMed  Google Scholar 

  55. Beron, W., Gutierrez, M. G., Rabinovitch, M. & Colombo, M. I. Coxiella burnetii localizes in a Rab7-labeled compartment with autophagic characteristics. Infect. Immun. 70, 5816–5821 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Swanson, M. S. & Isberg, R. R. Association of Legionella pneumophila with the macrophage endoplasmic reticulum. Infect. Immun. 63, 3609–3620 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Gutierrez, M. G. et al. Autophagy is a defense mechanism inhibiting BCG and Mycobacterium tuberculosis survival in infected macrophages. Cell 119, 753–766 (2004).

    CAS  PubMed  Google Scholar 

  58. Nakagawa, I. et al. Autophagy defends cells against invading group A Streptococcus. Science 306, 1037–1040 (2004).

    CAS  PubMed  Google Scholar 

  59. Ogawa, M. et al. Escape of intracellular Shigella from autophagy. Science 307, 727–731 (2005).

    CAS  PubMed  Google Scholar 

  60. Liang, X. H. et al. Protection against fatal Sindbis virus encephalitis by beclin, a novel Bcl-2-interacting protein. J. Virol. 72, 8586–8596 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Orvedahl, A. et al. HSV-1 ICP34.5 confers neurovirulence by targeting the Beclin 1 autophagy protein. Cell Host Microbe 1, 23–35 (2007).

    CAS  PubMed  Google Scholar 

  62. Tallóczy, Z., Virgin, H. W. & Levine, B. PKR-dependent autophagic degradation of herpes simplex virus type 1. Autophagy 2, 24–29 (2006).

    PubMed  Google Scholar 

  63. Dengjel, J. et al. Autophagy promotes MHC class II presentation of peptides from intracellular source proteins. Proc. Natl Acad. Sci. USA 102, 7922–7927 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Paludan, C. et al. Endogenous MHC class II processing of a viral nuclear antigen after autophagy. Science 307, 593–596 (2005).

    CAS  PubMed  Google Scholar 

  65. Rubinsztein, D. C. et al. Autophagy and its possible roles in nervous system diseases, damage and repair. Autophagy 1, 11–22 (2005).

    CAS  PubMed  Google Scholar 

  66. Ravikumar, B., Duden, R. & Rubinsztein, D. C. Aggregate-prone proteins with polyglutamine and polyalanine expansions are degraded by autophagy. Hum. Mol. Genet. 11, 1107–1117 (2002).

    CAS  PubMed  Google Scholar 

  67. Hara, T. et al. Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 441, 885–889 (2006).

    CAS  PubMed  Google Scholar 

  68. Komatsu, M. et al. Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 441, 880–884 (2006).

    CAS  PubMed  Google Scholar 

  69. Boya, P. et al. Inhibition of macroautophagy triggers apoptosis. Mol. Cell Biol. 25, 1025–1040 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Yu, L. et al. Regulation of an ATG7–beclin 1 program of autophagic cell death by caspase-8. Science 304, 1500–1502 (2004).

    CAS  PubMed  Google Scholar 

  71. Sugawara, K. et al. The crystal structure of microtubule-associated protein light chain 3, a mammalian homologue of Saccharomyces cerevisiae Atg8. Genes Cells 9, 611–618 (2004).

    CAS  PubMed  Google Scholar 

  72. Rubinsztein, D. C., Gestwicki, J. E., Murphy, L. O. & Klionsky, D. J. Potential therapeutic applications of autophagy. Nature Rev. Drug Discov. 6, 304–312 (2007).

    CAS  Google Scholar 

  73. Gozuacik, D. & Kimchi, A. Autophagy and cell death. Curr. Top. Dev. Biol. 78, 217–245 (2007).

    CAS  PubMed  Google Scholar 

  74. Meijer, A. J. & Codogno, P. Signalling and autophagy regulation in health, aging and disease. Mol. Aspects Med. 27, 411–425 (2006).

    CAS  PubMed  Google Scholar 

  75. Nobukuni, T., Kozma, S. C. & Thomas, G. hvps34, an ancient player, enters a growing game: mTOR Complex1/S6K1 signaling. Curr. Opin. Cell Biol. 19, 135–141 (2007).

    CAS  PubMed  Google Scholar 

  76. Gordon, P. B. & Seglen, P. O. Autophagic sequestration of [14C]sucrose, introduced into rat hepatocytes by reversible electro-permeabilization. Exp. Cell Res. 142, 1–14 (1982).

    CAS  PubMed  Google Scholar 

  77. Kawamata, T. et al. Characterization of a novel autophagy-specific gene, ATG29. Biochem. Biophys. Res. Commun. 338, 1884–1889 (2005).

    CAS  PubMed  Google Scholar 

  78. Stasyk, O. V. et al. Atg28, a novel coiled-coil protein involved in autophagic degradation of peroxisomes in the methylotrophic yeast Pichia pastoris. Autophagy 2, 30–38 (2006).

    CAS  PubMed  Google Scholar 

  79. Bergamini, E. Autophagy: a cell repair mechanism that retards ageing and age-associated diseases and can be intensified pharmacologically. Mol. Aspects Med. 27, 403–410 (2006).

    CAS  PubMed  Google Scholar 

  80. Melendez, A. et al. Autophagy genes are essential for dauer development and life-span extension in C. elegans. Science 301, 1387–1391 (2003).

    CAS  PubMed  Google Scholar 

  81. Shimizu, S. et al. Role of Bcl-2 family proteins in a non-apoptotic programmed cell death dependent on autophagy genes. Nature Cell Biol. 6, 1221–1228 (2004).

    CAS  PubMed  Google Scholar 

  82. Liu, Y. et al. Autophagy regulates programmed cell death during the plant innate immune response. Cell 121, 567–577 (2005).

    CAS  PubMed  Google Scholar 

  83. Schmid, D. & Münz, C. Immune surveillance of intracellular pathogens via autophagy. Cell Death Differ. 12, 1519–1527 (2005).

    CAS  PubMed  Google Scholar 

  84. Singh, S. B., Davis, A. S., Taylor, G. A. & Deretic, V. Human IRGM induces autophagy to eliminate intracellular mycobacteria. Science 313, 1438–1441 (2006).

    CAS  PubMed  Google Scholar 

  85. Kuma, A. et al. The role of autophagy during the early neonatal starvation period. Nature 432, 1032–1036 (2004).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

I thank P. Codogno, B. Levine, F. Meijer, N. Mizushima and P. Seglen for their comments, and apologize to those researchers whose work could not be cited due to space limitations. This work was supported by a grant from the US National Institutes of Health.

Author information

Authors and Affiliations

Authors

Ethics declarations

Competing interests

The author declares no competing financial interests.

Supplementary information

Supplementary information S1 (movie) | Autophagosome formation

The formation of an autophagosome is visualized by monitoring a green fluorescent protein (GFP)-ATG5 fusion protein in mouse embryonic stem cells through time-lapse video microscopy (5 minutes elapsed time). ATG5 localizes on the phagophore membrane during elongation and dissociates from the membrane upon completion of autophagosome formation. Movie provided by Noboru Mizushima (Tokyo Medical and Dental University). (AVI 599 kb)

Related links

Related links

DATABASES

Entrez Genome Project

Mycobacterium tuberculosis

Streptococcus pyogenes

FURTHER INFORMATION

Daniel J. Klionsky's homepage

Autophagy journal homepage

AscB image and video Library

Rights and permissions

Reprints and permissions

About this article

Cite this article

Klionsky, D. Autophagy: from phenomenology to molecular understanding in less than a decade. Nat Rev Mol Cell Biol 8, 931–937 (2007). https://doi.org/10.1038/nrm2245

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrm2245

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing