Autophagy

Autophagy Introduction

“My message for young generation … Be free from authority and common sense, and develop original interests and questions …”​

 Yoshinori Ohsumi
Tokyo Institute of Technology, Tokyo, Japan
 
Awarded with the 2016 Nobel Prize in Physiology or Medicine „for his discoveries of mechanisms for autophagy“.
 

About Autophagy

Definition

Autophagy describes a process where eukaryotic cells degrade cytoplasmic material in the lysosomal compartment.

Significance

Autophagy is an essential cytoprotective process that provides various opportunities for adaptive responses to cellular insults, such as starvation. As such, autophagy is a survival mechanism and fulfills important roles in development, differentiation, immunity and pathogen defense. Autophagy is further considered to contribute to life-span extension, and autophagy dysregulation has been found to foster the pathogenesis of many human diseases.

Autophagy Lecture

Sharon Tooze will present the keynote lecture on „Early Events in Autophagosome Formation”  at the GBM/DGZ Fall Conference in Tübingen, Germany,
25th through the 27th September 2019.
Please register and come to Tübingen!
Sharon Tooze on “Molecular Mechanisms of Autophagy”.
to the channel

Term

The term “autophagy”, literally meaning “self-eating” when translated from Greek, was coined by Christian de Duve in 1963.

Christian de Duve (2 October 1917 – 4 May 2013)
Awarded with the Nobel Prize in Physiology or Medicine 1974, together with Albert Claude and Georg E. Palade,  „for their discoveries concerning the structural and functional organization of the cell.“

Interview Part on Autophagy: Self-eating by cells

Major Forms of Autophagy

Three major forms of autophagy have been recognized:

  • Macroautophagy, characterized by the formation of autophagosomes that deliver cytoplasmic material to the lysosomes,
  • Microautophagy, characterized by direct engulfment of cytoplasmic material through lysosomal membrane invagination,
  • Chaperone-mediated autophagy, characterized by the degradation of proteins in lysosomes mediated by the chaperone Hsc70, co-chaperones and the lysosomal receptor LAMP2A.
“Experimental researches made on animals subjected to a more or less absolute privation of food have shown that life may be maintained for a certain period at the expense of the substance of the organs, as is proved by the progressive diminution of the weight of the animal suffering from inanition. This mode of nutrition has long been termed autophagy…” Auselmier M. on Nutrition by Blood in Starvation, Selections from Foreign Journals, in Progress of Medical Science p98,1860.
 
E. Karanasios and N.T. Ktistakis, Autophagy at the Cell, Tissue ans Organismal Level, SpringerBrief in Cell Biology, DOI 10.1007/978-3-319-33145-4_1

… which the cell undergoes membrane rearrangements to

  • sequester a portion of cytoplasm (cargo)
  • degrade the cargo (by fusion with lysosomes/vacuole)
  • recycle the macromolecular constituents. 

Suggested reviews

Morishita H, Mizushima N. Diverse Cellular Roles of Autophagy. Annu Rev Cell Dev Biol. Vol 35, October 7, 2019. 

Dikic I, Elazar Z. Mechanism and medical implications of mammalian autophagy. Nat Rev Mol Cell Biol. 2018, 19(6):349-364.

Ktistakis NT, Tooze SA. Digesting the expanding mechanisms of autophagy. Trends Cell Biol. 2016, 26(8):624-635. 

Klionsky DJ et al., Guidlines for the use and interpretations of assays for monitoring autophagy (3rd edition). Autophagy. 2016 12(2):443.

 

Füllgrabe J, Ghislat G, Cho DH, Rubinsztein DC. Transcriptional regulation of mammalian autophagy at a glance. J Cell Sci.. 2016, 129(16):3059-66. 

Ohsumi Y. Historical landmarks of autophagy research. Cell Res. 2014, 24(1):9-23. 

Mizushima N, Levine B, Cuervo AM, Klionsky DJ. Autophagy fights disease through cellular self-digestion. Nature. 2008, 451(7182):1069-75. 

Klionsky DJ. Autophagy: from phenomenology to molecular understanding in less than a decade. Nat Rev Mol Cell Biol. 2007, 8(11):931-7. 

The process of macroautophagy

Autophagosome Formation

During the process of macroautophagy (herafter: autophagy), cytoplasmic material, including organelles, proteins, lipids and membranes, becomes sequestered in unique double-membrane vesicles, called autophagosomes. The sequestration of cytoplasmic material occurs either stochastically or due to specific cargo recognition. Autophagosomes are formed by the elongation and closure of a membrane template, referred to as isolation membrane or phagophore.

Subsequently, autophagosomes acquire acidic hydrolases from the fusion with lysosomes, thereby forming the so-called autolysosome. Monomers of the degraded cargo are finally shuttled to the cytoplasm for recycling or storage. Autophagy is active on a constitutive low basal level, but rapidly elevated upon a great variety of cellular insults.