Chapter 2 - Molecular Machinery and Genetics of the Autophagy Pathway

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The macroautophagy (autophagy) pathway is an ancient and highly conserved intracellular process that occurs in most eukaryote cells. We now understand that autophagy is a complex cellular stress response pathway that serves to sequester and transport intracellular components to the lysosome for degradation and recycling. The unique double-membrane feature of the autophagosome vesicles was characterized over 50 years ago from detailed transmission electron microscopy ( TEM ) imaging studies 1. ; 2. ; 3. . Mutational studies done with yeast starting in the 1990s first characterized the molecular components required to initiate the production and completion of new autophagic vesicles ( AV ) or autophagosomes 4. ; 5. ; 6. ; 7. . Subsequently, molecular genetic studies done in worms, fruit flies and mice have characterized the high level of conservation that occurs among different pathway components. Identification of new factors only found in multicellular organisms underscores the intricate role that autophagy plays in complex physiological processes. The pathway requires the input of two parallel conjugation systems that are centered around two ubiquitin-like proteins called Atg8/MAP-LC3 and Atg12 8. ; 9. . In addition, there is the Atg9:Atg18:Atg2 trafficking system that appears to selectively recruit lipid components to the growing phagophore membrane. Pathway activation and regulation of autophagosome formation requires input from both the Atg1/ULK1 10. ; 11. protein kinase initiation complex as well as a phosphatidylinositol 3-kinase (PI3K) complex 12. ; 13. ; 14. . As additional molecular components of the pathway are identified there is a growing understanding that selective forms of autophagy play significant roles in the maintenance and function of different tissue types, including the nervous system (aggrephagy) and the heart (mitophagy). Insight into the function of autophagy in human disease processes is undergoing a rapid period of growth as our understanding of the role that metabolic disorders (i.e. type-II diabetes and metabolic syndrome) have on long-term autophagic function.