You come home from a weekend away. You can’t wait to jump into your slippers, put your feet up and settle down with your favourite show. *sniff sniff* You start to notice a weird smell and after a few seconds of detective work you realize you didn’t take out the garbage before you went and it stinks to high heaven!
Anyone who has ever had roommates knows that everyone has different levels of tolerance for how often this dull but necessary chore must occur but most of us agree it does have to happen eventually! Your cells agree and they too must make time to take out the trash. This process is known as autophagy.
What is autophagy?
Autophagy comes from the Greek for “self-eating”. It is the regulated digestion by a cell of its own damaged or unneeded components via the autophagosomal-lysosomal pathway. This self-digestion is a recycling process that allows cells to reuse materials and it is particularly useful in times when a cell is starved of nutrients.
Even the most fastidious roommates don’t take out every piece of trash as it is created. It’s fine for it to go into a container to be taken out in bulk. This is also true of the cell’s trash. Cells mark damaged or worn out components for digestion but there is always a few bits and pieces floating around it that could be recycled, such as senescent mitochondria. In times of starvation when the cell is not getting sufficient nutrients, these unmarked components will also be digested as the cell attempts to scavenge for needed proteins, carbohydrates and lipids and meet its energy needs. An interesting example of this is in newborn mice after the maternal nutrient supply from the placenta ceases and autophagy is increased.
Like with the balance between taking out the trash before it stinks and not being accused of being the world’s most nagging roommate, this process of autophagy occurs in a balance: not too often and not too infrequently. Interestingly, it is thought that aging and certain disorders and conditions may be caused in part by a failure of the body to maintain autophagy. What better way to get sick than to accumulate large amount of trash! Such conditions include Alzheimer’s, cancer and Parkinson’s. Where autophagy is too prolific, a cell could actually end up destroying itself; however, so this balance is key!
Cells can change the number and size of autophagosomes to increase and reduce the cell’s capacity to conduct autophagy. Where nitrogen, amino acid, oxygen and sugar levels are high, autophagy levels are low. When levels of any of these are low, key regulator will activate autophagy..
What are the types of autophagy?
There are three main types of autophagy (and one more specific type) and each plays an important role in the proper development and maintenance of the body. Macroautophagy is the main pathway used. Autophagy is executed by autophagy-related (Atg) genes. More than 25 different proteins have been identified in yeast and animal cells that participate in the process.
|Macroautophagy||A double membrane known as the autophagosome is formed around the organelle marked for destruction.
This autophagosome moves through the cytoplasm to a lysosome, and the two organelles fuse.
The contents of the autophagosome are degraded by the lysosome using acidic lysosomal hydrolases.
|Microautophagy||Material to be degraded are engulfed directly into the lysosome.
This process occurs via invagination, inward folding of the lysosomal membrane to create a pocket.
It is then digested by lysosomal enzymes.
|Chaperone-mediated autophagy (CMA)||Chaperones recognize, unfold and translocate certain proteins in the cytosol for destruction without the need for vesicle formation. Chaperones identify particular amino acid sequences on the protein called a CMA-targeting motif. These chaperones are known as heat shock cognate protein of 70 kDa (hsc70).|
|Mitophagy||This is a specific form of autophagy limited to the degradation of mitochondria. Mitochondria subjects to mitophagy are often damaged or defective.|
What is autophagy used for?
- Obsolete or damaged organelles, like peroxisomes and mitochondria can be selected for degradation and their components used to make other organelles. This limits the accumulation of damaged and unused cellular components and enables the developing body to restructure cells e.g. the selective elimination of paternal mitochondria post-fertilization.
- When the body is subjected to reduced nutrient levels, the digestion of certain cellular components, both damaged and undamaged, enables cells to better weather poor conditions.
- In defending the body against pathogens, autophagy is used to destroy bacteria and viruses that gain access to the cell or are detected externally. Whole organelles or large aggregated of protein can be removed easily. This process is used particularly in phagocytes like macrophages and neutrophils.
Can autophagy be used as a treatment in disease?
Long story short, maybe!
Autophagy dysregulation can be seen in aging, metabolic diseases, neurodegenerative disorders, infectious diseases and cancer. However while is some stages of a condition, autophagy is inhibited at other times is in increased. It is thought that the increase of autophagy promotes longevity and many cancer treatments have been found to increase autophagy. In neurodegenerative diseases like Alzheimer’s disease, proteins accumulate to form aggregates or inclusions in the intracytoplasmic and/or extracellular space. It is thought that by increasing autophagy less of these protein clumps will form. However, where a component of the autophagy process is defective, such as the delivery of autophagosome to lysosomes, increasing autophagy may not be beneficial and instead may cause the accumulation of autophagosomes in the cell. In addition, autophagy is also thought to be essential for tumor progression and malignancy.
It is clear more research is needed in this area but for now it remains a promising new avenue for treatment discovery.
Targeting autophagy as a strategy for drug discovery and therapeutic modulation
Autophagy modulation as a potential therapeutic target for diverse diseases