The Autophagy is an intracellular degradation system occurs so preserved in the lysosomes of all eukaryotic cells (and vacuoles yeasts). The word is generally used to refer to the degradation of the components of the cytosol or the “parts” of the cell that are “obsolete” or that have stopped working properly.
The term autophagy was coined in 1963 at Rockefeller University by de Duve, who also observed and described the processes of cellular endocytosis. Literally, the word autophagy means “to consume oneself”, although some authors describe it as “self cannibalism”.
This system differs from proteasome-mediated degradation in that autophagy is capable of removing complete intracellular organelles and large protein complexes or aggregates in a non-selective manner.
Despite this non-selective phagocytosis, different investigations have shown that autophagy has numerous physiological and pathological implications. Since it is activated during periods of adaptation to starvation, during development, for the elimination of invading microorganisms, during programmed cell death, for the elimination of tumors, the presentation of antigens, etc.
Autophagy, as discussed, is a process mediated by a cytoplasmic organelle known as the lysosome.
The process of “autophagy” begins with the encapsulation of the organelle that will be degraded by a double membrane, forming a membranous body known as the autophagosome. The autophagosome membrane subsequently fuses with the lysosomal membrane or with a late endosome.
Each of these steps between the sequestration, degradation and release of amino acids or other components for recycling exerts different functions in different cellular contexts, which makes autophagy a highly multifunctional system.
Autophagy is a fairly controlled process, since only the marked cellular components are directed towards this degradation pathway and the marking generally occurs during cellular remodeling processes.
For example, when a liver cell establishes a detoxification response in response to fat-soluble drugs, its smooth endoplasmic reticulum proliferates considerably, and when the stimulus generated by the drug decreases, the excess smooth endoplasmic reticulum is removed from the cytosolic space by autophagy.
Induction of autophagy
One of the events that most commonly triggers autophagic processes is starvation.
Depending on the organism under consideration, different types of essential nutrients can trigger this “recycling” system. In yeast, for example, although the carbon deficiency of certain amino acids and nucleic acids can induce autophagy, the nitrogen deficiency is the most efficient stimulus, which is also valid for plant cells.
Although it is not fully understood, cells have special “sensors” to determine when a nutrient or essential amino acid is in very low condition, and thus trigger the entire recycling process through lysosomes.
In mammals, some hormones participate in the regulation (positive or negative) of autophagy in cells belonging to certain organs, such as insulin, some growth factors or interleukins, etc.
There are three main types of autophagy among eukaryotes: macro autophagy, micro autophagy, and chaperone-mediated autophagy. Unless specified, the term autophagy refers to macro autophagy.
Although the three types of autophagy are morphologically different, they all end in the transport of substances to lysosomes for degradation and recycling.
This is a type of autophagy that depends on the de novo formation of phagocytic vesicles known as autophagosomes. The formation of these vesicles is independent of the formation of membrane “buds”, since they are formed by expansion.
In yeast, the formation of autophagosomes begins at a particular site known as the PAS, while in mammals many different sites occur on the cytosol, probably linked to the endoplasmic reticulum through structures known as “omegasomes”.
The size of autophagosomes is highly variable and depends on the organism and the type of molecule or organelle that is phagocytosed. It can vary from 0.4-0.9 μm in diameter in yeast to 0.5-1.5 μm in mammals.
When the membranes of the autophagosome and the lysosome fuse, the content of these is mixed and that is when the digestion of the target substrates of autophagy begins. This organelle is then known as the autolysosome.
For some authors, macroautophagy can be subclassified, in turn, into induced autophagy and baseline autophagy. Induced macroautophagy is used to produce amino acids after a prolonged period of starvation.
Basal macroautophagy refers to the constitutive mechanism (which is always active) essential for the turnover of the different cytosolic components and intracellular organelles.
This type of autophagy refers to the process in which the cytoplasmic content is introduced to the lysosome through invaginations that occur in the membrane of said organelle.
Once introduced into the lysosome, the vesicles produced by these invaginations float freely in the lumen until they are lysed and their content is released and degraded by specific enzymes.
This type of autophagy has only been reported for mammalian cells. Unlike macro-autophagy and micro-autophagy, where some cytosolic portions are non-specifically phagocytosed, autophagy mediated by chaperones is quite specific, since it depends on the presence of particular pentapeptide sequences in the substrates that will be phagocytosed.
Some investigators have determined that this pentapeptide motif is related to the KFERQ sequence and that it is found in more than 30% of cytosolic proteins.
It is called “chaperone-mediated” since chaperone proteins are responsible for keeping this conserved motif exposed to facilitate its recognition and prevent the protein from folding on it.
Proteins with this tag are translocated to the lysosomal lumen and are degraded there. Many of the degradation substrates are glycolytic enzymes, transcription factors and their inhibitors, calcium- or lipid-binding proteins, proteasome subunits, and some proteins involved with vesicular trafficking.
Like the other two types of autophagy, chaperone-mediated autophagy is a regulated process at many levels, from label recognition to transport and degradation of substrates within lysosomes.
One of the main functions of the autophagic process is the removal of senescent or “stale” organelles, which are tagged by various routes for degradation within lysosomes.
Thanks to the observation of electron microphotographs of lysosomes in mammalian cells, the presence of peroxisomes and mitochondria has been detected in them .
In a liver cell, for example, the average life span of a mitochondrion is 10 days, after which this organelle is phagocytosed by lysosomes, where it is degraded and its components are recycled for different metabolic purposes.
Under conditions of low nutrient concentration, cells can trigger the formation of autophagosomes to selectively “capture” portions of the cytosol, as well as the digested metabolites in these autophagosomes can help cells survive when external conditions are limiting from the point of view. from a nutritional point of view.
Roles in health and development
Autophagy has important functions in the restructuring of cells in the process of differentiation, since it participates in the discarding of cytosolic portions that are not required at specific times.
It also has important implications for cellular health, as it is part of the defense mechanisms against invading viruses and bacteria.
Yoshinori Ohsumi Studies
Yoshinori Ohsumi, a 2016 Nobel Prize-winning Japanese researcher in Physiology and Medicine, described the molecular mechanisms of autophagy in yeast while studying the metabolic fate of many proteins and the vacuoles of these single-celled organisms.
In his work, Ohsumi not only identified the proteins and the pathways involved in the process, but also demonstrated how the autophagy pathway is regulated thanks to the action of proteins capable of “sensing” different metabolic states.
Their work began with precise microscopic observations of the vacuoles during intense degradation events. Vacuoles are considered the storage sites for yeast “garbage” and cellular debris.
By observing yeasts with defective mutant genotypes for different genes related or hypothetically related to autophagy (known as ATG genes ), this researcher and his collaborators were able to describe the autophagic system of yeast at the genetic level.
Subsequently, this group of researchers determined the main genetic characteristics of the proteins encoded by these genes and made significant contributions about their interaction and the formation of the complexes responsible for the initiation and execution of autophagy in yeast.
Thanks to the work of Yoshinori Ohsumi, today we better understand the molecular aspects of autophagy, as well as its important implications in the correct functioning of the cells and organs that make us up.
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