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Autophagy in Cells: Facts, Mechanisms, Benefits, and Problems

Linda Crampton is a science writer and teacher with a first-class honors degree in biology. She finds human and cell biology fascinating.

This illustration of a human cell shows some important organelles. The lysosomes play a vital role in autophagy.

This illustration of a human cell shows some important organelles. The lysosomes play a vital role in autophagy.

The Nature and Purpose of Autophagy

Autophagy is a useful process in cells that is sometimes referred to as "self eating." The process involves the destruction of items in a cell with the aid of lysosomes. The items that are destroyed include damaged organelles and other structures, pathogens (microbes that cause disease), and protein molecules that have formed clumps and are no longer functional.

Autophagy is a complex activity that involves the action of many genes and the proteins that they code for. Though the process is normally helpful for us, this isn't always the case. Researchers have discovered links between the dysregulation of autophagy and some major health problems.

Autophagy is often difficult to study. Specialized equipment is necessary and scientists with experience are required in order to interpret some of the data. Fortunately, researchers are gradually increasing their knowledge of the process. Their discoveries could be very important with respect to our health.

Features of Lysosomes

Based on our current knowledge, three major types of autophagy exist. All of them require the presence of an organelle known as a lysosome and the enzymes that it contains. An organelle is a specialized structure in a cell that performs a specific task or related tasks. Enzymes increase the rate of chemical reactions, enabling them to be helpful for living things.

There may be hundreds of lysosomes in a cell. They play a central role in autophagy because the cell components that are removed are broken down inside the lysosomes (or in a hybrid structure made from a lysosome and another organelle).

Each lysosome is a spherical vacuole surrounded by a single membrane. It contains hydrolytic enzymes, which break down molecules in an acidic environment. Hydrogen ions are moved into a lysosome to produce the acidic pH. A lysosome is reusable. It isn't destroyed when its contents disintegrate.

Autophagy Discovery, Research, and Types

In 2016, Yoshinori Ohsumi (born in 1945) won the Nobel Prize for Physiology and Medicine for the discovery of the mechanisms of autophagy. Though he has learned important details about how autophagy works, he didn't discover the process. Autophagy was discovered by Christian de Duve (1917–2013), a Belgian scientist. He created the name "autophagy" in the 1960s. Little was known about the process until Ohsumi's discoveries began in the 1990s.

De Duve paved the way for later autophagy studies in another way. He discovered lysosomes. He won the Nobel Prize for Physiology and Medicine in 1974 with two other scientists for discoveries related to the "structural and functional organization of the cell.” One of the discoveries was the existence of the lysosome.

The three major categories of autophagy are macroautophagy, microautophagy, and chaperone-mediated autophagy (or CMA). Macroautophagy appears to be the the most important type, though this may be a false assumption based on inadequate knowledge.

Macroautophagy

Macroautophagy is the only type of autophagy that requires another organelle in addition to the lysosome. The extra organelle is known as an autophagosome. It's not a permanent structure but is made when needed. The process is summarized in the image above.

  • In the initiation phase, a double-membraned vacuole forms. It surrounds the items to be destroyed as it's being created. The vacuole is called a phagophore as it forms. When it's completely formed, it's called an autophagosome.
  • The autophagosome fuses with a lysosome. The united structures form an autolysosome.
  • Within the autolysosome, structures and molecules are broken down by enzymes. Some of the products are recycled and are released into the cell for reuse.

Mitophagy is the destruction of mitochondria and is considered to be a specialized type of macroautophagy. Mitochondria are the organelles that produce most of the energy required by a cell.

Autophagy is a strategy for cellular self-fortification, but it is also a balance: too much or too little autophagy can be harmful to the cell.

— Vivian Marx, via Nature Methods

Additional Types of Autophagy

Macroautophagy is the best studied type, but two additional kinds of autophagy exist and are being explored.

Microautophagy

In microautophagy, an invagination or pocket forms in the membrane of the lysosome. The item to be destroyed or recycled enters the lysosome via the invagination, which eventually forms a small sac known as a vesicle. The lysosome then breaks the item down.

Microautophagy seems to perform some of the same jobs as macroautophagy. At the moment, it's not clear whether it occurs at the same time as the latter process or whether it operates when that process is inactive.

Chaperone-Mediated Autophagy

Chaperone-mediated autophagy is also known as CMA. It operates by a different mechanism from the other two methods. A chaperone protein carries the cell component through the membrane of the lysosome and into its interior, where the component is destroyed.

Autophagy Problems and Disease

Autophagy is an important process for maintaining the health and even the life of a cell. Both excessive and impaired autophagy can be dangerous, however. Problems with the process have been linked to specific health problems. Two of these problems are intestinal inflammation and Parkinson's disease.

Autophagy also appears to play a role in cancer, but it has different effects depending on the specific type of cancer that is being studied and perhaps on other factors. Cancer cells are abnormal and have altered behavior compared to normal cells. In some lab experiments, stimulating autophagy has been found to be helpful for dealing with cancer, while in others it has been found to be harmful.

Stimulating and inhibiting autophagy as necessary may eventually be useful treatments for some health problems. We need to learn more about how the process works in different types of cells and in different conditions, however.

Part of the intestinal mucosa with its protective white blood cells and chemicals and the lumen (central passageway) of the intestine

Part of the intestinal mucosa with its protective white blood cells and chemicals and the lumen (central passageway) of the intestine

Maintaining a Healthy Intestinal Mucosa

Autophagy helps to keep the digestive tract healthy. Food passes through the digestive tract from the mouth to the anus. On the way, it's broken down into small molecules that act as nutrients. These are absorbed into the bloodstream through the lining of the intestine, or the mucosa. The remaining food leaves the body as feces.

The mucosa is a very important layer of the intestinal wall. It contains multiple cells types that have major roles in absorption or in maintaining the health of the intestine. Autophagy helps to keep the mucosa intact and in good condition. The process is activated in some of the mucosal cells to destroy the bacteria and other microbes that they absorb from the intestine. It also helps to keep Paneth cells heathy.

The Paneth cells are located in the glands or crypts of the small intestine. The illustration above shows a flattened mucosa without crypts. Paneth cells secrete antimicrobial peptides, including lysozyme and alpha-defensins, which help to keep the lining of the intestine in good condition. Their name is derived from that of a scientist called Joseph Paneth and is therefore capitalized.

Autophagy is required to maintain anti-microbial defense, epithelial barrier integrity and mucosal immune response.

— Sabah Haq et al, Journal of Biological Science

The Nature of Genes and Mutations

Specific genetic problems can cause problems with autophagy. Researchers have discovered that certain mutations (changes in the structure of genes) are linked to Crohn's disease, which is a type of inflammatory bowel disease. "Bowel" is another name for intestine. The disease causes inflammation of the mucosa.

Genes

Genes contain instructions for making proteins. The instructions are provided in the form of a sequence of chemicals called nitrogenous bases. These bases are part of a deoxyribonucleic acid or DNA molecule. Scientists often say that DNA "codes" for proteins. A single DNA molecule codes for multiple proteins. Each section of a DNA molecule that contains instructions for making a particular protein is called a gene.

Mutations

An alteration in the sequence of nitrogenous bases in a gene (a mutation) can interfere with the instructions for making a protein and cause problems. Mutations can be caused by certain chemicals and types of radiation, the activity of particular viruses in the cell, mistakes made during cell replication, and inheritance via the egg or sperm used to create an individual.

Mutated Genes and Crohn's Disease

Genes That Affect Autophagy

Researchers have found a group of genes that are important in autophagy. They call them ATG genes (autophagy-related genes) and have given each one a number. They've discovered that people with a problem in their ATG16L1 gene have an increased risk of developing Crohn's disease (CD). The name of the gene is sometimes written in small letters. Other genes in the series are believed to be involved in the disease as well. CD can be a major problem for the sufferer.

An Altered Protein

According to the National Institutes of Health, the defective ATG16L1 gene causes an altered protein to be made, which impairs autophagy. This allows damaged cell parts and harmful bacteria to continue to exist instead of being destroyed. Their presence may trigger an "inappropriate" immune response, which causes inflammation of the intestinal mucosa.

Compensating for the Change

Researchers are exploring ways to compensate for the dysfunctional protein or proteins involved in CD. As they say, since autophagy occurs in multiple cell types around the body, the potential body-wide effect of any drug that modifies the process must be taken into account. The research might eventually yield some wonderful benefits for people with an inflamed intestinal lining, but we're not at that stage yet.

In neurodegenerative conditions, for example, compromised autophagy is considered a contributor to neuronal cell death. That makes it tempting to explore how one might upregulate autophagy in a patient. But before that can happen, basic biology research on autophagy is needed.

— Vivian Marx, via Nature Methods

Neurons and Parkinson's Disease

Alpha-Synuclein Tangles

In Parkinson's disease, dopamine-producing neurons in a part of the brain called the substantia nigra die. Dopamine is a neurotransmitter, or a chemical that transmits a nerve impulse from one neuron to another. At least some of the neurons that die contain Lewy bodies. These bodies contain tangles of a protein called alpha-synuclein. The relationships between the observed brain changes in Parkinson's disease and the effects of the changes are still being studied.

The Possible Benefit of Autophagy

One team of researchers (referenced below) has found that autophagy is impaired in the brains of both Parkinson's and Alzheimer's disease patients. The brains of patients with the latter disease also contain tangled proteins, some of which are inside cells. The scientists would like to stimulate autophagy in order to break up the proteins in a patient's brain and are investigating ways to do this. The situation might not be as straight forward as it sounds in Parkinson's disease because scientists have found that Lewy bodies contain more than just alpha-synuclein. It certainly seems that the treatment is worth investigating, though.

Activating the Parkin Enzyme

Parkin is an enzyme that prepares substances for degradation in lysosomes. The researchers found that in cell cultures and in lab animals, drugs that activate the enzyme can lead to activation of autophagy and the removal of neurotoxic proteins. Drugs that can activate parkin might be useful in treating some human diseases. As is true for the other illnesses mentioned in this article, however, further research is necessary. It's vital that after autophagy has been activated or increased and has been helpful, it's decreased or stopped (as required) to prevent injury to healthy structures.

Autophagy in Cancer

In lab experiments, scientists have found that autophagy can prevent tumor initiation in at least some kinds of cancer. They have also found that it can promote the survival of some pre-existing tumors, however. This is an area where further research is vital. Stimulating autophagy might be useful in some types and stages of cancer and inhibiting it may be useful in others.

One type of cancer in which there are hopeful signs related to autophagy is pancreatic cancer. The video above was created by the Huntsman Cancer Clinic at the University of Utah. Researchers at the clinic (and other scientists) have found that almost 90% of patients with pancreatic cancer have a mutation in a gene called KRAS. They say that the mutated gene constantly sends signals that cause abnormal cell division and tumor formation in the pancreas. The cancer cells depend on autophagy to remove damaged or harmful components so that the cells can remain active.

The researchers have found that in mice a treatment that targets both the effects of the gene mutation and the autophagy problem is beneficial and "shows a strong response" in the animals. Experiments in mice don't always apply to humans, but they sometimes do.

An enlarged section of a human cell (Major cell structures are shown, but others exist. Cells are complex structures.)

An enlarged section of a human cell (Major cell structures are shown, but others exist. Cells are complex structures.)

Research Difficulties

Autophagy can be difficult to study. Experience is needed to tell that a structure seen in an electron micrograph (a picture made with the aid of an electron microscope) is actually a phagosome. If a chemical related to autophagy is discovered in living cells or if it's found to be increasing in quantity, researchers need to confirm that the observation is actually due to the process of autophagy. Working at the subcellular level can be difficult. It's encouraging that the scientific interest in autophagy is increasing and that the number of researchers exploring the topic seems to be increasing, though.

Hope for the Future

The situation is tantalizing for scientists. The have seen enough evidence to convince them that successful or impaired autophagy is involved in some important situations in our body, but the details of what is happening are proving hard to determine. It's important that scientists discover all of the steps involved in normal autophagy and understand the nature of the problems in the abnormal process. The discoveries would be very interesting and might help many people.

References

  • Information about lysosomes from the British Society for Cell Biology
  • Lysosome facts from the National Human Genome Research Institute
  • Relevant Nobel prize awards from the Nobel Prize website
  • Types of autophagy from the Encyclopedia Britannica
  • Autophagy: eat thyself, sustain thyself by Vivian Marx in Nature Methods
  • Autophagy in intestinal mucosal homeostasis and inflammation from the Journal of Biomedical Science
  • Information about the ATG16L1 gene and Crohn's disease from the U.S. National Library of Medicine
  • Facts about Parkinson's disease from the Mayo Clinic
  • A link between autophagy problems and Parkinson's disease from The Conversation (written by a neurologist)
  • The role of autophagy in cancer from Annual Review of Cancer Biology
  • Information about autophagy and cell death from the Nature journal

This content is accurate and true to the best of the author’s knowledge and is not meant to substitute for formal and individualized advice from a qualified professional.

© 2020 Linda Crampton

Comments

Linda Crampton (author) from British Columbia, Canada on September 27, 2020:

Hi, Mary. I hope that further studies enable us to treat diseases, too. That would be a wonderful outcome of the research.

Mary Norton from Ontario, Canada on September 27, 2020:

Linda, this is fascinating and I hope that future development will make us understand better the effects of autophagy especially in the brains of those with Parkinson's and other diseases.

Linda Crampton (author) from British Columbia, Canada on September 26, 2020:

Thank you very much, Flourish. I hope better treatments for the disorders are found soon, too. I hope you're having a good weekend.

FlourishAnyway from USA on September 26, 2020:

This was a well researched deep dive into the topic for the layperson. You always provide such fascinating information. I hope better treatments and cures are in sight for these diseases.

Linda Crampton (author) from British Columbia, Canada on September 26, 2020:

Hi, Mel. Yes, it's important that researchers understand how an individual cell works. It's a fascinating and very important topic.

Linda Crampton (author) from British Columbia, Canada on September 26, 2020:

I'm so sorry to hear about your niece's son-in-law, Peggy. I hope he recovers soon. The virus is creating some horrible problems. Thank you for the comment.

Mel Carriere from San Diego California on September 26, 2020:

It just goes to show you how complex the human body is, that these tiny cells coexist alongside to create a complete organism. And to understand it, we have to come to grips with how each cell functions individually, instead of looking at the system as a whole.

Once again, I learned something new by reading your articles.

Peggy Woods from Houston, Texas on September 26, 2020:

This is a fascinating article, per usual from you. I wonder if this could have anything to do with my niece's son-in-law being newly diagnosed with gastroparesis due to his contracting of COVID. He is only 37 and may have to be on a feeding tube for the rest of his life if they cannot get medications to kick in and be effective. So far, they have had no success, and he is wasting away. Very sad!

I hope that further research will end up with remedies for other diseases.

Linda Crampton (author) from British Columbia, Canada on September 26, 2020:

I appreciate your comment, Heidi. I hope people with Crohn's and other health problems are helped by the research.

Linda Crampton (author) from British Columbia, Canada on September 26, 2020:

Hi, Bill. The research began before 2016. It is fascinating. Improved techniques will hopefully make the research easier. I'm looking forward to seeing what else is discovered.

Heidi Thorne from Chicago Area on September 26, 2020:

This is way above my intellectual pay grade when it comes to biology. But fascinating nonetheless.

My dad had Crohn's. So any developments on that front are encouraging. Back when he was young, the only way to deal with it was major surgery for damage caused by the disease. Now we have amazing drugs to help manage it, even though those can have side effects, too. Hope the autophagy research offers even more avenues for treating it.

Thanks for always sharing your deep knowledge of the biological world with us!

Linda Crampton (author) from British Columbia, Canada on September 26, 2020:

Thank you for the comment, Chitrangada. I appreciate your visit very much.

Bill Holland from Olympia, WA on September 26, 2020:

I assume it wasn't until 2016 that these things were discovered because technology had to be developed which would allow for the discovery? This stuff absolutely amazes me. I don't understand but a small fraction of it, but it is still fascinating.

Chitrangada Sharan from New Delhi, India on September 26, 2020:

Excellent and informative article.

This is a well researched article, about Autophagy in cells, with some crucial details.

Thanks for the education, through this well presented article.

Linda Crampton (author) from British Columbia, Canada on September 25, 2020:

I appreciate your comment very much, Umesh.

Umesh Chandra Bhatt from Kharghar, Navi Mumbai, India on September 25, 2020:

Excellent article. Though I had biology only up to my high school, I would be gaining a lot from this article but one simple reading would not suffice and I would come back to it later. Like your other articles it is very elaborate and well researched. Thanks.

Linda Crampton (author) from British Columbia, Canada on September 25, 2020:

Thank you very much for the comment, Eric. There are many questions linked to autophagy. I'm interested in seeing what else researchers discover about the process and its effects.

Eric Dierker from Spring Valley, CA. U.S.A. on September 25, 2020:

Extremely interesting and thorough. I could not help but wonder if this has a mental factor to it. It seems it could actually lead to an imbalance of cells needed for emotional stability - too much too little. I wonder just how much energy is consumed in such processes.(processi)

Very well done.

Linda Crampton (author) from British Columbia, Canada on September 25, 2020:

Hi, Pamela. Like you, I hope cures or at least better treatments for the conditions that you've mentioned appear soon. Thank you for the comment.

Pamela Oglesby from Sunny Florida on September 25, 2020:

As abnormaities inl autophagy are linkd to intestinal inflammation and Parkinson's disease I hope cures are not too far in the future. This was a very technical article that must have been time consuming to write and I appreciate the work you have done. I read some of it more then once as I really want to understand the processes in the body. Thanks, Linda.