Everything You Wanted to Know About Autophagy

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What is Autophagy

Autophagy is the regulated process by which a cell degrades its dysfunctional or unnecessary components. The cell can then recycle the useful chemical components for further purposes within the cell [R,R2].

Autophagy is necessary because there are continuously molecular processes going on within the cell and errors occur.

This process only occurs in eukaryotic cells (animal cells and other cells with membrane-bound components), not in prokaryotic cells (bacteria and other cells without membrane-bound components) [R].

Autophagy can remove misfolded proteins, damaged organelles (organized structures within the cell), and pathogens also within the cell.

Therefore, autophagy is a protective process for the cell. Autophagy can protect  the cell from/prevent against many diseases, including cancer, heart disease, liver disease, diabetes, and many other infections.

Nutrient starvation is one of the most primary causes of autophagy because it provides substrates to sustain the cell [R].

Additionally, autophagy helps maintain energetic efficiency within the cell.

The 3 different types of autophagy include macro-autophagy, micro-autophagy, and chaperone-mediated autophagy [R].

Tissues that require a lot of energy are more dependent on autophagy, including the brain, liver and muscle [R].

How Does Autophagy Occur

Autophagy is triggered by damage, starvation, oxidative stress, or pathogens within the cell.

Autophagy occurs through the action of Lysosomes. Lysosomes are components of animal cells and some plant cells that contain degradative enzymes (proteins that are biological catalysts) contained within a fluid-filled sac. Lysosomes must be contained within a membrane to ensure that only the necessary cellular components are destroyed [R].

First, an isolation membrane (phagophore) engulfs the intracellular components that need to be removed or destroyed. Once the isolation membrane matures into a double-membraned autophagosome, it fuses with the lysosome.

The Lysosome contains the necessary lysosomal acid proteases for cleavage and degradation.

Following the degradation, the useful by-products of the cell enter the cytoplasm where they can be reused to build other molecules or for other metabolic processes [R].

Macroautophagy

Macroautophagy is the most common form of Autophagy.

Macro= large-scale. This process occurs in bulk so many proteins and/or organelles are degraded at the same time.

There is a protein within the cell called TOR (target of rapamycin) that usually helps to maintain and ensure metabolism and protein synthesis. However, when the cell is starving, TOR is blocked and thus cannot work.

When TOR is blocked, Macro-Autophagy is triggered.

Macroautophagy occurs in the same manner as Autophagy, which explains why the terms may be used synonymously.

Microautophagy

Microautophagy is different because the cellular components that need to be destroyed must directly enter the lysosome (fluid-filled membrane containing enzymes for degradation).

Stored glucose, proteins with the incorrect structure, and individual organelles can be destroyed through Microautophagy.

This process occurs in several steps. First, the lysosomal membrane forms tube(s) around the damaged cellular component. Then, the membrane closes around the damaged component, forcing the damaged components within the lysosome. The component can then be degraded.

Occasionally, a portion of the nucleus may undergo this process.

Chaperone-Mediated Autophagy

Chaperone-Mediated Autophagy is a process that only degrades damaged proteins in the cytosol (the liquid part of the cell).

A sequence (pattern) in the DNA recognizes the damaged protein.

The damaged parts are guided into the lysosome by a “chaperone.” In biology, a chaperone is a protein that assist the cell. In this case the chaperone is a heat shock protein (hsp70).

A specific protein (LAMP-2A) on the lysosomal membrane acts as a receptor and allows the chaperone and the damaged protein complex  to attach to the the lysosomal membrane.

Then the LAMP-2A receptor protein changes its shape to allow the damaged protein to enter inside the lysosome and it also prevents the damaged protein from leaving before it is destroyed.

Once the protein is destroyed, the amino acids it is made of can return to the cytosol again [R].

Autophagy Improves Muscle Performance

Autophagy is extremely important in maintaining the body’s equilibrium state, as well as the equilibrium state of muscles.

During exercise, as energy is used, damaged cell components, such as mitochondria, build up. This is because mitochondria is the sight of energy generation in the cell. Then, damaged cells also begin to accumulate.

A study using mice found that artificially induced Autophagy can help prevent this cell death and build up [R].

Exercise stimulates autophagy so that damaged cells can be cleared away.

Additionally, Chaperone-Mediated Autophagy helps muscles contract [R].

Blocking autophagy from occurring in mice caused the skeletal muscle fibers to degenerate [R].

Thus, autophagy after exercise promotes muscular health.

Disruptions To Autophagic Pathways Are Usually Harmful

Autophagy declines with age in almost all cells and tissues. The autophagic pathway also becomes increasingly dysfunctional.

The decline in autophagy that comes with age is thought to contribute to the onset of diseases associated with old age [R].

Disruptions to the autophagic pathway can be associated with many diseases, including but not limited to- cancer, neurodegeneration (degradation of the brain cells- diseases such as Parkinson’s, Alzheimer’s and Huntington’s), microbial infections, and metabolic dysfunctions [R].

A study, using rats, found that genetically manipulating the systems to prevent age-related decline of the systems allowed for healthier cells and tissue, confirming that disruptions to autophagy do in fact contribute to aging and diseases [R].

Autophagy Involvement in Cancer Prevention

Autophagy can help prevent cancer because it destroys and recycles damaged cells and/or their components.

A study using mice found that autophagy deficiency in mice causes benign liver tumors. This indicates that autophagy may be important to suppress tumor initiation in the liver. However, the study also indicates that autophagy may be required for the tumor to change from benign (non- harmful) to malignant (harmful) [R].

Lack of autophagy causes oxidative stress and genetic instability, which are factors known to cause cancer and the progression of cancer.

Lack of autophagy may also stimulate tumor growth by activating a nuclear factor involved in antioxidant defense.

P62 is a protein that accumulates when autophagy does not occur, and it induces a cellular stress response. p62 accumulation may also be a leading cause for cancer without autophagy due to the oxidative stress it causes and p62’s role in maintaining oncogenic pathways  [R, R2].

Autophagy’s Role in the Growth of Cancer

Autophagy is decreased at the beginning of tumor development. Conversely, autophagy can also promote the growth of cancer cells in later stages as a protective mechanism against the stressful conditions.

This is because cells in the central area of the tissue have less access to nutrients and autophagy helps them to survive.

Many types of cancer undergo autophagy due to nutrient starvation including colon cancer, breast cancer, melanoma, hepatoma and malignant glioma cells.

Other cancers have an ocogenic RAS transformation that prevents nutrient-starvation induced autophagy from occurring  [R].

Autophagy’s Role in Cancer Treatment

Methods that induce autophagy can be used in the therapeutic treatment of cancer.

Gamma irradiation and Hyperthemia are 2 therapeutic treatment methods that can induce autophagy in cancer cells, causing them to die.

However, in other cases autophagy in response to therapeutic treatment is a survival mechanism and does not cause cell death.

The type of cancer plays a vital role in whether therapeutic treatments using autophagy will be successful or not [R].

Autophagy Genes

A study using yeast found that there are at least 32 genes involved in Autophagy, many of which are also conserved in mammals. These genes are referred to as “Atg” genes  [R].

In yeast, a pre-autophagosomal (PAS) structure is required, but not in mammals, where the phagophore comes from the Endoplasmic Reticulum (a component of the cell).

Many Atg genes are required for phagophore formation in yeast.

In mammals, Vps34 (vesicular protein sorting 34) and Atg6/Betlin 1 are involved in phagophore formation [R].

ATG genes include:

Conclusions

It is clear that autophagy plays a vital role in maintaining normal cellular and tissue health, through maintaining energetic function and the destruction of anomalies within the cell.

Further research is being done to determine more about how autophagy can play a role in fighting age and disease [R].

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