Autophagy: Self-Repair Mechanism at Cellular Level

What is Autophagy?

Autophagy is the self-devouring mechanism of the body's cells, as a part of the normal physiological process involving cell death and disassembling of the by-products and dysfunctional components of the cells. The process ensures orderly degradation and proper utilization of the cellular components that are released in the process of cell death.

"Auto" means self and "phagy" means to eat. Thus the process that involves cell death, where the cell eats up some parts of itself, reuses some of it components and discards the waste. The process of autophagy is regulated by autophagy-related proteins located inside the cell.

Autophagy can be selective or non-selective in separating the specific organelles and removing the debris. Autophagy also causes apoptosis, also known as programmed cell death (PCD). Autophagy, in its non-apoptosis form, helps in maintenance of homeostasis.

Lysosomes are the organelles found inside each cell that contain acidic hydrolases that degrade the unwanted organelles and other cell components. That is the reason they are known by several names: "suicide bags of the cell", "scavengers of cell", "digestive bags of cell" or "garbage bags of the cell".

Autophagy may have possible defects like causing neurodegeneration (loss of structure and function of nerve cells) and tumorigenesis (formation of tumors). The autophagic vacuole is formed by the lysosome, just before the degradation of the digestible contents. Sometimes these vacuoles are not cleared up and can cause certain disease conditions.

Autophagy breaks down the unwanted components of the cell into amino acid components. The levels of amino acids increase in early stages of starvation, and are broken down by the liver into glucose. They may also be synthesized into new proteins.

What are the Types of Autophagy?

The basic process of autophagy is initiated by nutrient starvation in smaller organisms. In mammals, the process and its regulation is highly complicated. Three pathways of autophagy are usually seen in mammals.

The types of autophagy are categorized according to the processes the cell undergoes to destroy and recycle its components.

Macroautophagy - Macroautophagy is the main pathway, and the term autophagy usually refers to this process unless otherwise specified. The main purpose of this process is to eradicate cellular organelles that are damaged and the proteins that are unused.

The organelle that is marked for destruction is covered by a special membrane called autophagosome. This structure travels through the cytoplasm of the cell to fuse with a lysosome. The contents of the autophagosome are then degraded by acidic lysosomal hydrolases which are the enzymes found inside the lysosome.

Microautophagy - In this process, the debris is directly engulfed by the lysosome without the formation of autophagosome. The lysosome folds inwards or protrudes out to take in the unwanted organelle and degrades it.

Chaperone-mediated autophagy (CMA) - Hsv70 is a heat shock protein or a chaperone protein in the cytoplasm that binds to substrate proteins to be destroyed. Hsv70 then aids in the unfolding of the protein (a prerequisite to cross the lysosomal membrane) and translocation across the membrane into the lysosomal lumen to get degraded.

What are the Functions of Autophagy at Cellular Level?

Autophagy is an effective mechanism that plays a major role in cleaning up, defense and embryonic development.

• Cleaning up - The process of autophagy regulates the degradation and removal of damaged cell organelles, cellular components and removal of aggregated proteins or erroneously formed proteins from the cell's cytoplasm.
• Defense against invasion - Infected cells or cells that are invaded by foreign objects or microbes are killed in the process of autophagy.
• The process of autophagy maintains a balance between protein synthesis and protein degradation. This balance prevents various kinds of diseases like myopathy, liver disease, diabetes and neurodegenerative diseases.
• Takes part in cellular stress response - Cellular stress occurs when an organism undergoes various molecular changes in response to physical, toxic or thermal stimulants. Cells also undergo changes due to infection and diseases like cancer and ischemia.
• Development of embryo - During embryonic development a critical balance of energy levels and sources is well maintained by the process of autophagy.

What is the Role of Autophagy in Human Beings?

Since autophagy is a process that is initiated by nutrient depletion and involves regulation of the dead components at the cellular level, it plays a major role in human health and disease conditions.

Autophagy and Diet - Most of the diet programs involve calorie restriction in which there is intermittent fasting. Such diet programs boost autophagy and help in weight reduction.

Certain diet programs need to be followed for longer period of time.

High protein diet can stop or minimize autophagy while a high-fat, low carbohydrate diet can boost autophagy.

About 40 to 70 grams of protein per day (subject to lean body mass) is recommended to keep autophagy going.

A diet high in healthy fats and low in non-fiber carbohydrates can help boost autophagy.

Autophagy and Caloric Restriction versus Intermittent Fasting - Autophagy is initiated by nutrient deficiency at the cellular level. When the individual is on a low calorie diet, damaged components of the cell and broken proteins are destroyed and recycled.

Intermittent fasting is the opposite of calorie restriction where the individual consumes normal amount of calories on a regular basis, but fasts intermittently on a weekly or fortnightly basis. Fasting increases the levels of glucagon that stimulates the process of autophagy.

Autophagy cleanses the cells and takes away the junk, the accumulation of which is known to be responsible for effects of aging.

High calorie diet can induce excessive autophagy wherein amino acid production increases. The liver breaks them down to glucose and causes increase in the blood glucose levels.

Autophagy and Exercise - Exercise causes cellular disturbances like oxidative stress and energy imbalance. Metabolism in the cells is maintained through the process of autophagy by degrading the unwanted components and reusing materials such as amino acids. Autophagy is induced by exercise as a means of survival mechanism in times of heavy exercise.

A study mentions that when autophagy was artificially induced after exercise in mice, the cellular homeostasis was maintained by accumulation of damaged organelles in specific muscle fibers. Autophagy was shown to improve muscle metabolism and maintain muscle homeostasis during exercise.

The amount of exercise required to trigger autophagy is not yet established. Further, how much of autophagy process is considered to be healthy requires further investigations.

Exercise induced autophagy is also known to prevent or restore muscle loss that occurs due to aging process.

Autophagy and Osteoarthritis - Osteoarthritis is one of the age-related disease that is linked to autophagy. The proteins that are involved in autophagy reduce with age and lead to the structural damage of cartilage cells.

Autophagy and Cancer - Autophagy has a dual function in cancer - it may protect against cancer by suppressing tumor or contribute to the growth of cancer by aiding in tumor cell survival.

Autophagy at the cellular level helps to protect against formation of tumor cells by limiting necrosis, reducing oxidative stress and preventing chronic inflammation.

Cellular energy production when maintained at high levels by the process of autophagy can enable growth of tumor cells. This energy production then inhibits autophagy genes in the tumor cells. This in turn increases oxidative stress, genome instability and cancer progression.

Inhibition of autophagy in liver can cause chronic cell death in the liver and cause liver cancer. Inhibition of autophagy in tumor cells with chemotherapy can enhance tumor cell death.

Tapping on the potential of chemically induced autophagy in cancer cells opens up new avenues for cancer treatment.

Autophagy and Parkinson's Disease - Death of the cells in the brain and some of the brain stem cells are partially responsible for Parkinson's disease. Some of the genes like PINK1 and Parkin are found to be non-functional in Parkinson's disease. This can lead to accumulation of damaged mitochondria and protein aggregates and consequently cellular degeneration. This kind of dysregulation of cells in the nerves leads to neurodegeneration.

Autophagy and Alzheimer's disease - Autophagy-lysosome defects have been seen to occur in early stage of Alzheimer's disease and are thought to be the main contributor of the condition. However, there is a lot more to be explored about the connection between autophagy and Alzheimer's disease and therapeutic strategies can be worked out.

Health Tips

• Regular exercise is known to optimize autophagy, apart from increasing longevity. An average of 150 to 450 minutes of moderate exercise is recommended per week.
• Calorie-restricted diet is found to help in autophagy, thereby cleansing the body from the cellular level. However, consuming very limited amount of calories can cause damage to the cells.
• In case of a heavy meal in an unavoidable situation, follow a low-calorie diet after the heavy meal.
• Limit the amount of proteins in your diet to about 40 to 60 grams a day. Excessive proteins are known to inhibit autophagy.
• Lower stress levels as they cause disturbances at the cellular levels to inhibit autophagy.

References:

1. Autophagy: cellular and molecular mechanisms - (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2990190/)
2. Autophagy: process and function - (http://genesdev.cshlp.org/content/21/22/2861.full)
3. Cell �Self-Eating� (Autophagy) Mechanism in Alzheimer�s Disease - (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2835623/)
4. The Importance and Practical Application of Autophagy in Human Health - (https://www.lakeforest.edu/live/news/5512-the-importance-and-practical-application-of?preview=1)

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