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No use, distribution or reproduction is permitted which does not comply with these terms. The enzymes in the resulting compartment, an autolysosome, break down the inner membrane from the autophagosome and degrade the cargo. The resulting macromolecules are released and recycled in the cytosol. Autophagy: from phenomenology to molecular understanding in less than a decade.
Nature Reviews Molecular Cell Biology 8, — doi All rights reserved. It is depicted as an empty, oviform membrane in the cytoplasm.
As the phagophore develops, it forms a double membrane arranged in a half-moon crescent shape that encapsulates material in the cell cytoplasm. The green portion of the phagophore membrane is facing the encapsulated material, and the blue portion of the phagophore membrane is facing the exterior cytoplasm. The material to be encapsulated is three purple ovals, three smaller purple circles, and an orange oval representing a mitochondrion. To the right of this, after a rightward-pointing arrow, the phagophore forms an enclosed, circular vesicle around the material.
The phagophore is surrounded by a double membrane, green on the inside and blue on the outside. When a phagophore engulfs cytoplasm that includes cell debris and organelles, the circular vesicle is called an autophagosome.
A section of the double membrane is shown at a higher magnification in an inset illustration and looks like pairs of dots with a squiggle line in between them, forming a ladder-like object. The blue and green ladders are arranged vertically and next to each other in the inset. The three purple ovals, three smaller purple circles, and orange oval are now inside the autophagosome.
The autophagosome transports engulfed cell material to a lysosome, where it is degraded by lysosomal enzymes.
Here, the lysosome is depicted as an enclosed, circular vesicle with a single, pink membrane. Six small, blue squiggly lines inside the lysosome represent acid hydrolase enzymes. Three pink spheres attached to the outside of the single membrane represent permease enzymes. An upward and rightward arrow from the lysosome joins the rightward arrow from the autophagosome and points toward the fusion of the autophagosome with the lysosome, forming an autolysosome, which contains both the enzymes from the lysosome and the material from the autophagosome.
It looks like two conjoined circles, with the lysosome on the left, except that the blue and green membranes of the autophagosome have been broken. Material imported into the cell from the external environment can also be transported to a lysosome and degraded. Along the membrane pocket are five brown circles and a group of purple ovals and circles from outside the cell that are encapsulated in an invagination of the cell membrane and imported into the cell cytoplasm. This fusion creates an amphisome.
The amphisome looks very similar to the autophagosome, except there is a break in the blue membrane in the nine 'o clock position, where the endosome attaches, forming a three-quarters circle similar to the endocytosis pocket. A down and rightward arrow from the amphisome and a down and leftward arrow from an unlabeled lysosome to the right merge together, where the amphisome fuses with a lysosome to form an autolysosome.
The autolysosome, which can contain either an autophagosome and a lysosome or an autophagosome, endosome, and lysosome, begins to degrade its interior components. The autolysosome is depicted as a blue ring with three blue circles on the border, a dashed green circle interior to the purple one, and what looks like the digested pieces of the three pink ovals, three smaller pink circles, and an orange oval.
In , Yoshinori Ohsumi and his colleagues at the University of Tokyo discovered that autophagy also occurs in yeast.
Using a light microscope, they noticed that a few hours after starving yeasts of nutrients, the vacuole which functions like our lysosomes was filled with vesicles containing chunks of cytoplasm.
These vesicles originate in the cytoplasm and then fuse with the lysosome, exactly as in animal and plant cells. Being able to use yeasts as an experimental model opened the door for studying the molecular biology of the autophagic machinery and for identifying the key proteins that participate in the process Takeshige et al.
In , fifty years after Novikoff and de Duve observed lysosomes under the electron microscope, Noboru Mizushima and colleagues at the Tokyo Medical and Dental University tracked the formation of autophagosomes by taking pictures every five minutes. For their experiments, they used a fluorescently-labeled protein that localizes specifically in phagophores and observed the real-time formation of autophagosomes Klionsky see video, Figure 2.
One mystery that remained unanswered for many years was: which membrane in the cell gives rise to phagophores? In , Jennifer Lippincott-Schwartz and her colleagues used fluorescently-labeled proteins to study the origin of phagophores. How much and what parts of the cell can be eaten without causing cell death? Scientists hypothesized that the level of autophagy and the cargo specificity must be tightly controlled to ensure the cell's health. For example, when there are plenty of nutrients, the autophagy level should be low, but autophagy must increase upon starvation.
For unicellular organisms, it is essential to maintain a pool of metabolites, such as amino acids. Therefore, starvation-induced autophagy was likely selected first in unicellular organisms, and later retained in multicellular organisms. In mammals, autophagy is not only induced by starvation, but also by physiological stimuli, such as growth factors and hormones, as well as by pathogen invasion. In general, autophagy is used to engulf non-specific components, but it can also selectively degrade damaged organelles, pathogenic inclusions, or invasive bacteria Nakatogawa et al.
Therefore, autophagy likely evolved as a response to cell starvation, and later it probably served as a primitive immune defense. The process of autophagy occurs all the time, whether a cell is starving or not, but at a basal level. Under normal conditions autophagy removes damaged proteins and organelles to prevent cell damage. However, under stress e. Under these conditions, intracellular molecules are digested to provide the nutrients the cell needs. These discoveries have led many scientists around the world to study the diverse physiological functions of autophagy.
Currently, there are over 2, publications about autophagy, and several recent findings have linked this cellular process with immune and metabolic diseases. There are still many fundamental questions about the mechanisms governing autophagy that must be addressed. Many scientists believe that studying autophagy regulation is critical to understanding its biological role and to developing alternative therapies for diseases associated with autophagy dysregulation.
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