Autophagy

=Macroautophagy, Microautophagy, and Organelle Specific Autophagy=

Autophagy
The basic catabolic mechanism that involves cell degradation of unnecessary or dysfunctional cellular components through the action of lysosomes. This ensures cellular survival during starvation by maintaining cellular energy levels. If regulated, autophagy ensures the synthesis, degradation and recycling of cellular components.

3 Types of Pathways Involved in Autophagy:
__Macroautophagy__- it is the main pathway that occurs mainly to eradicate damaged cell organelles or unused proteins. When autophagy is induced a double membrane forms around cytoplasmic substrates resulting in the organelle known as the autophagosome. The autophagosome travels through the cytoplasm of the cell to a lysosome and the two organelles fuse together and the intersection with endosomal pathways occurs. Within the lysosome the contents of the autophagosome are degraded using acidic lysosomal hydrolases.

__ Microautophagy __ - Involves the direct engulfment of cytoplasmic material into the lysosome. The lysosomal membrane folds inward which is also known as cellular protrusion.

__Organelle-Specific Autophagy (Chaperone-Mediated Autophagy)-__ Is a very complex and specific pathway which involves the recognition by the hsc70-containing complex. The protein must contain the recognition site for this hsc70 complex which allows it to bind to this chaperone. The complex then moves to the lysosomal membrane-bound protein that will recognize and bind with the receptor allow it to enter the cell. The substrate protein then gets unfolded and translocated across the lysosome membrane with the assistance of the lysosomal hsc70 chaperone.

Discovery of Lysosomes and Autophagy:
In 1949, Christian de Duve was studying how insulin acted on liver cells. He wanted to determine the location of a specific enzyme inside of the cells and he knew that this specific enzyme played a role in regulating blood sugar levels. Christian de Duve and his research group obtained cellular extracts by blending rat liver fragments in distilled water and centrifuging the mixture at high speeds. When they tried to purify the enzyme from cellular extracts, the group ran into a problem. They could precipitate the enzyme, but they couldn't redissolve it. After many experiments they hypothesized that a membrane-like barrier limited the accessibility of the enzyme to its substrate. An experienced microscopist was able to obtain the first electron micrographs of the new organelle which was the lysosome. In the following years, researchers studied many different types of cells using electron microscopes and discovered a wide variety of vesicles. Some of the vesicles contained engulfed cytoplasmic material. Some scientists suggested these particular vesicles were pre-lysosomes.

Autophagy and Disease:
Autophagy disorders have been linked to neurodegenerative diseases because of the misfolded protein aggregates. An example is Alzheimer’s disease. Autophagy has been linked to Alzheimer’s disease pathogenesis through its merger with the endosomalysosomal system, which has been shown to play a role in the formation of the latter amyloid-β plaques.

Research:
__Selective autophagy mediated by autophagic adapter proteins (2010):__ This article suggests that autophagy is a more selective process than originally determined. This paper reviews that basis of selective autophagy in mammalian cells discussing the degradation of misfolded proteins, p62 antibodies, aggresomes, mitochondria and invading bacteria.

__Jun proteins inhibit autophagy and induce cell death (2010):__ This article shared that some genes that have been induced by serum and growth factors can inhibit autophagy.

__The autophagy initiating kinase ULK1 is regulated via opposing phosphorylation by AMPK and mTOR (2011):__ This article discusses ULK1, which is a serine/threonine kinase that is a mammalian homolog of Atg1, that is yeast is regulated in mammals by AMPL and mTORC1.

References:

Castro-Obregon, S. The discovery of lysosomes and autophagy. Scitable. 2010. []

Egan D, Kim J, Shaw RJ, Guan K. The autophagy initiating kinase ULK1 is regulated via opposing phosphorylation by AMPK and mTOR. Autophagy 2011; 7:643 - 644; PMID: 21460621; []

Funderburk, S., Marcellino, B., Yue, Z. Cell “Self-Eating” (Autophagy) Mechanism in Alzheimer’s Disease. Mount Sinai Journal of Medicine. 2010. []

Johansen T, Lamark T. Selective autophagy mediated by autophagic adapter proteins. Autophagy 2011; 7:279 - 296; PMID: 21189453; []

Yogev O, Shaulian E. Jun proteins inhibit autophagy and induce cell death. Autophagy 2010; 6:566 - 567; PMID: 20404571; []