Autophagy

Autophagy


Did you ever get so hungry, that you ate yourself? (No would be the right answer). But sadly, your body does indeed eat itself, just at a cellular level. This phenomenon is autophagy, which literally translates to “self-eating.” [Auto- self; phagy- eating]

Autophagy is a process in which a cell eats its own components. It is the basic catabolic mechanism that involves cell degradation of unnecessary or dysfunctional cellular components through the action of lysosomes. It therefore involves the delivery of cytoplasmic materials to the lysosome for degradation.

We did discuss this already under, “Waste Disposal in Cells” as being one of the mechanisms of action of lysosomes, and a very important one at that.

You must still be wondering though – Why would my cell eat components of itself? What even? They have no chill.

Well, truth of the matter is, every component within a cell has its own needs. The more organelles within the cell, the greater its metabolism since more energy would be needed to sustain the cell. So when there is a deficiency of nutrients, or an inability to sustain this high metabolism by the body, the cell begins to destroy components within itself so as to decrease the metabolism to levels the body can afford to supply. We say this is decreasing nutrient demand to match nutrient supply.

Classes of Autophagy:

Needless to say, there are several different organelles that can be consumed via autophagy, and this leads to different types of autophagy, very easily explained:

I bet this was easier than you thought it would be.

Yes, if autophagy involves a mitochondrion, it is called mitophagy, a peroxisome – pexophagy, protein aggregates – aggrephagy, glycogen – glycophagy, lipids – lipophagy.

The only one that will need special attention is xenophagy, which will be explained in detail later.

Types of Autophagy:

Note the difference here, between the classes of autophagy and the types of autophagy, as they refer to completely different things. While the classes of autophagy refer to the particular substance broken down in the autophagy process, the type of autophagy refers to the mechanism by which autophagy occurs.

With this in mind, it can be said that there are 3 types of autophagy:

  1. Chaperone-mediated Autophagy: This is the direct transport of a protein or molecule across the lysosomal membrane and into the lysosome by a  chaperone protein on the wall of the lysosomal membrane. This type of autophagy is extremely specific, because it is completely determined by a complex known as the hsc70 complex. The hsc70 recognition complex is present on the lysosomal hsc70 chaperone, and if the protein that comes into contact with this chaperone contains a recognition site for hsc70, then it is rapidly chaperoned towards the lysosome, where it binds to a receptor for this chaperone and shuttles the protein or substance across the lysosomal membrane and into the lysosome.
  2. Microautophagy: This is the engulfment of cytosolic substances by direct inward invagination of the lysosomal membrane. This means that the lysosome itself invaginates and consumes nearby substances.
  3. Macroautophagy: This is classically referred to simply as autophagy, and is thus recognized as the most important and largest type of autophagy. It involves the sequestration and transport of portions of cytosol in a double-membrane compartment called a autophagosome, towards a lysosome.

Mechanism of Macroautophagy:

Macroautophagy, or simply autophagy is the major method of the destruction of organelles, and can be easily simplified into several steps:

  1. Activation of an initiation complex that induces the formation of an isolation membrane, called a phagophore. This process is stimulated by environmental cues that promote autophagy, such as starvation. This activates the initiation complex which is really a complex of 4 proteins that stimulates the formation of a nucleation complex.
  2. Nucleation of the phagophore, which refers to the short period or short wait during which the phagophore is assembled.
  3. Assmebly of the phagophore, and its subsequent elongation.
  4. As the phagophore elongates, it slowly encloses components within the cytoplasm and cytosol, including small cellular debris and large organelles.
  5. Fusion of the two ends of the phagophore, which causes its maturation into an autophagosome. This elongation and closure of the autophagosome depends on the coordinated action of several ubiquitin-like conjugation systems, including, a very important microtubule associated protein light chain 3, LC3. LC3 determines the contents that are being loaded onto the autophagosome as it is being formed. The synthesis of LC3 is increased in cells carrying out autophagy, and thus LC3 level is the most important way to detect when the cell is undergoing autophagy.
  6. Fusion of the autophagosome with a lysosome to form an autophagolysosome.
  7. Degradation of internal contents of the autophagolysosome alongside its inner membrane, completing macroautophagy.

The formation of the autophagosome is arguably the most crucial stage of macroautophagy. Regulating this process are more than a dozen “autophagy related genes” or Atgs.

Typically, autophagosomes cannot recognize what they enclose without the LC3, and engulfing is usually random. However, there are certain exceptions, and the autophagosomal membrane is able to recognize certain molecules, the most important of which is in the Cvt pathway, explained in detail in the next section. Briefly, if the autophagosomal membrane recognizes two enzymes, called Ams1 or Ape1, then the autophagosome does not fuse with the lysosome, but instead carries the enzymes to vacuoles where the enzymes have effects. This is explained further lower down, no worries!

Importance of Autophagy:

The main reason has been discussed already. The main reason a cell will opt for autophagy is when nutrient supply is low, and the cell must decrease nutrient demand to match nutrient supply. Initially, if nutrient supply is only low for a very short period of time, most of the protein breakdown is done by the ubiquitin-proteasome system. If the nutrient supply is delayed for a long period of time, then autophagy comes into action. After organelles are degraded, they will not exert a metabolic effect on the cell, and this allows the cell to survive as nutrients made available can be more efficiently delegated. In addition, some of the proteins and peptides extracted from broken down organelles can be recycled to produce more important cell products that promote cell survival, via process such as energy production, gluconeogenesis and synthesis of more essential proteins. Just to bring this point home, studies conducted on yeast cells that have genes for autophagy mutated very rapidly die in nutrient-deficient conditions.

The other reasons are as follows:

  1. Xenophagy: Xenophagy is a process whereby foreign pathogens that are within the cell, can be removed from the cell. Xenophagy literally means foreign eating [Xeno- foreign, phagy-eating]. I know what you’re thinking now, “Isn’t Autophagy supposed to be self-eating?” Technically it still is, except the body directs the autophagy to include foreign matter or pathogens as well. It becomes extremely important in specific circumstances. Now consider the fact that some bacteria are able to prevent the fusion of a phagosome (from phagocytosis) to a lysosome to form a phagolysosome. In this scenario, the pathogen is free to wreak havoc on the cell as it sees fit. Autophagy mediated xenophagy can prevent this, as autophagy is rapidly stimulated to destroy any organelle the pathogen is housed in, or to consume the region of cytosol the pathogen is within. This prevents the pathogen from destroying the cell, and the organelle can easily be regenerated.
  2. Transport: Autophagy also allows the transport of substances via the Cvt pathway, for antigen presentation and TLR recognition.
    1. At times, autophagy can simply be used as a pathway or a method of transport from the cytosol to vacuoles or lysosomes. The best example of this is indeed the Cvt pathway in yeast cells. In the Cvt pathway in yeast cells, two important vacuolar enzymes, Ape1 and Ams1 are synthesized in the cytosol. These enzymes are apparently “swallowed” into a compartment consisting of a double layered membrane, called an autophagosome. The production of the autophagosome is a very important step of autophagy. However, the autophagosome delivers the enzymes to the vacuole, instead of to the lysosome, thereby allowing delivery or transport via autophagy.
    2. Furthermore, autophagy plays a role in antigen presentation. Endogenous peptides derived from phagocytosis or any form of pathogen degradation are delivered to the major histocompatibility complex class II (MHCII) via autophagy, where the antigens are detected by CD4+ T cells, an important part of the immune response.
    3. Finally, the autophagy pathway is used to recognize viral single stranded RNA (ssRNA). This is mediated by toll-like receptors (TLRs), which are key molecules in innate immunity that recognize markers on viruses to signal an immune response. One type of TLR is called TLR7, located on endosomes, recognizes viral products being delivered to it from other autophagosomes derived from the autophagy process. Thus, it can be seen that autophagy, though suggestive of a degradative process, can also act as a biosynthetic pathway, and simply as a means of transport.
  3. Sequestration: In some cases, sequestration or simple storage in autophagosomes without degradation seems to be an important process.
    1. Of special note is the ability of the cell to respond to ER (endoplasmic reticulum) stress. In scenarios of an overactive ER, the ER generates a very high metabolism that the cell is not able to handle to equal the nutrient supply. In addition the overactive ER may generate cytotoxic signals, which are signals that may alter the pH of the cytosol, or damage the cytosol. In these cases, the ER stress can be removed simply by engulfing a portion of the ER in an autophagosome. This sequestration blocks the ER stress and restores normal functioning of the cell.
    2. However, the fact that autophagy first requires the production of a harmless autophagosome before it can form the degradative autophagolysosome can be easily exploited by certain microorganisms, such as Legionella pneumophila, Coxiella Burnetti, Brucelus abortus and porphyromonas gingivalis. These bacteria are first stored in phagosomes obtained from phagocytosis, and these phagosomes fuse with autophagosomes to become stored in autophagosomes. Here, the bacteria are able to inhibit the fusion of the autophagosome to the lysosome, and thus have a well-protected, enclosed area to replicate in. This strategy for survival is referred to as the “pregnant pause” technique of survival.
  4. Elimination of Macromolecules and Organelles: Elimination of macromolecules and organelles is one of the major roles of autophagy. Misfolded proteins, damaged organelles and cell membranes are all destroyed by autophagy, although a significant amount of misfolded proteins are also degraded by the ubiquitin proteasome system. If this removal of cellular debris and cellular waste does not occur properly, it results in rapid aging, or if there are defects, then two major pathologic signs can occur.
    1. The first is neurodegeneration. The accumulation of autophagosomes is associated with several types of neurodegenerative diseases such as Alzheimer’s and Parkinson’s. It has been demonstrated in mice that damaging autophagy genes causes several neurodegenerative disorders. This is because autophagy removes defective proteins associated with neurodegerative disorders, such as the Tau protein as in the case of Alzheimer’s Disease.
    2. Secondly, a second pathology that can result is tumorigenesis. There are many accounts suggesting that autophagy acts to suppress tumor cells. High metabolic stresses can overwork the internal mechanisms of the cell and increases the likelihood of a random mutation resulting in the formation of a tumor cell. Autophagy, as explained, can decrease metabolic stress and decrease the likelihood of forming a tumor. Thus, deficiency in autophagy will call tumorigenesis.

There are also additional roles of autophagy in disease as shown:


That’s all guys! See if these extra resources can also help you out!

VIDEOS:

Autophagy (7:24)

Role of Autophagy (2:24)

EXTRA RESOURCES:

Research Study on Autophagy 

Robbins and Cotran’s Pathologic Basis of Disease.

QUESTIONS:

1. Which of the following is not a function of autophagy?

A. Transporting certain enzymes to their destination

B. Innate Immunity

C. Displaying antigens on an MHC I complex.

D. Preventing growth of cancerous cells.

2. Which of the following types of autophagy is the most specific form?

A. Macroautophagy

B. Microautophagy

C. Chaperone-mediated Autophagy

D. Aggrephagy

3. Which of the following bacteria cannot use the “pregnancy pause” technique of survival?

A. Legionella pneumophila

B. Brucelus abortus

C. Porphyromonas gingivalis

D. Coxiella Gilesi

4. A pathologist, after analyzing a sample from a patient Jane, finds an elevated levels of LC3 in her cells. The patient’s BMI was found to be 34. Which of the following could be happening within the patient?

A. The patient is undergoing a typical starvation response.

B. There is decreased ER stress within the patient.

C. Jane has been infected with a bacteria that prevents fusion of the phagosome with the lysosome in phagocytosis.

D. The patient has excessive organelle formation.

ANSWERS:  C (Remember, autophagy uses the MHC II complex), C, D, C.

[Why C for number 4? Remember, if phagocytosis cannot remove the pathogen, then autophagy takes over to destroy any organelles and membrane bound vesicles the pathogen may be housed in.]

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