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"Autophagy" literally means "Self-Eating" - but we're talking about self-eating that happens inside of individual cells. It's a process, found in plants, fungi and animals, where a cell "eats itself" a little bit - that is, wraps up some of its cytoplasm (the cell body) and sends it to the vacuole/lysosme (the stomach of the cell). Why? Sometimes, because it's starving, and this is the only way to survive. Other times, this is a way to get rid of broken bits inside the cell, which would otherwise be toxic.
In general, autophagy helps the cell to stay healthy - which means it helps you to stay healthy, too. Autophagy helps to prevent neurodegenerative diseases like Parkinson's and Alzheimers, helps fight off pathogens trying to take over your cells, and helps prevent some cancers. Sound interesting? I think so. Keep reading for more.
Autophagy and Human Health
Autophagy and Human Health
Like any biological process, autophagy has a complicated relationship with health, and whether it is good or bad depends on the exact circumstances. But for the most part, autophagy is good for your health. Some of its main health benefits include:
Helping prevent neurodegenerative diseases like Parkinson's and Alzheimer's by getting rid of broken, toxic cell components such as malfunctioning mitochondria and protein aggregates.
Helping fight intracellular pathogens, and preventing excessive inflammation
Autophagy is closely connected with the idea of caloric restriction: the finding that limiting the number of calories consumed, for example by dieting or fasting, can extend life span in many different organisms. Although it's not known for sure whether or not this works in humans, it seems likely that it does. Fasting isn't the only way to stimulate autophagy; exercise also turns it on. Exercising regularly and modestly limiting your calories are good for your health for a variety of reasons, but part of their benefits are probably due to stimulating autophagy and thus cleaning up your cells and reducing inflammation.
One method to stimulate autophagy that I personally practice is intermittent fasting. There's no proof that this practice has health benefits, and most of the claims you can find about it online are not well supported and should be taken with a grain of salt. However, I think it probably does have some benefits, and have decided to carry out that experiment on myself.
Autophagy is turned on by caloric restriction
Autophagy is turned on by caloric restriction
Further reading on autophagy in human health:
Khandia et al. "A Comprehensive Review of Autophagy and Its Various Roles in Infectious, Non-Infectious, and Lifestyle Diseases: Current Knowledge and Prospects for Disease Prevention, Novel Drug Design, and Therapy" Cells. 2019 Jul; 8(7): 674 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6678135/
Galluzzi et al. "Pharmacological modulation of autophagy: therapeutic potential and persisting obstacles" Nat Rev Drug Discov. 2017 Jul; 16(7): 487–511. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5713640/
Many scientists are also interested in finding drugs that can safely stimulate (or, in other cases, block) autophagy as possible treatments for disease. For example, people with genetically linked neurodegenerative diseases such as Huntington's disease would probably benefit from a drug that could stimulate autophagy; so might elderly individuals with Alzheimer's or other dementia, as autophagy naturally decreases as we get older. This is part of the reason for research on understanding how autophagy works - the better we understand it, the more likely we are to be able to make safe and effective medications targeting it.
Selective and Nonselective Autophagy
Selective and Nonselective Autophagy
There are a variety of different types of autophagy; my research (and all of the information this page) is about the process technically called "macroautophagy." This process in turn falls can be divided into two categories: selective autophagy and nonselective autophagy. Both use most of the same proteins, meaning that they must function in a very similar way. However, they have very different purposes for the cell.
Nonselective autophagy is all about recycling nutrients so that the cell can survive. This type of autophagy is mostly driven by starvation. It's called "nonselective" because its targets - the specific things in the cell that are getting sent to the vacuole/lysosome to be broken down - are more or less random. The cell is just "nibbling" on itself from the inside, and doesn't really care what it eats.
Selective autophagy, in contrast, isn't really about hunger. Instead, it's a way for the cell to get rid of specific things in the cytoplasm that should not be there by sending them to the vacuole/lysosome to be digested and destroyed. Selective autophagy is triggered by the presence of a specific target, and the different types are named by what that target is, as shown in the diagram above. For example, "xenophagy" is selective autophagy that targets foreign pathogens like Tuberculosis or Samonella that are trying to set up shop in your cell. "Mitophagy" targets damaged mitochondria that are poisoning your cells with reactive oxygen species, while "aggrephagy" targets protein aggregregates that are gumming up the cellular machinery.
Selective autophagy is happening in your cells all the time, helping to keep them clean and healthy. When you fast or exercise, this stimulates non-selective autophagy, but at the same time it also increases the rate of selective autophagy in your cells, potentially making them more efficient at getting rid of cellular debris and keeping them healthy for a longer time.
Autophagy and Cell Membranes
Autophagy and Cell Membranes
Autophagy is a process that happens in all eukaryotes - that is, all cells that have a nucleus, including plants, animals and fungi. All eukaryotic cells have a system of internal membrane compartments called the "endomembrane system." These membranes create distinct spaces within the cell where different process can occur: organelles such as the ER, Golgi, and lysosome/vacuole. They are also dynamic: moving around the cell, carrying cargo, fusing with each other and budding apart.
Autophagy is a part of the endomembrane system. "Autophagosomes" are large vesicles with a double membrane that engulf the cargo to be degraded and carry it to the vacuole/lysosome, which they then fuse with so that the cargo can be delivered and degraded. However, unlike many other parts of the endomembrane system, autophagosomes are not always present, but instead are created on demand. How this process of de novo autophagosome creation occurs has long been one of the big mysteries in the field of autophagy, although in just the last couple of years we are beginning to understand it.
My primary area of research interest since undergrad has been understanding the endomembrane system and how proteins control membrane dynamics. That's what brought me into studying autophagy, since it was one of the least understood endomembrane processes.
The endomembrane system
The endomembrane system
Simplified diagram of the eukaryotic endomembrane system, with example electron micrographs from a plant cell. Orange = membrane; Yellow = lumen (inside) of the endomembrane system. Green = cytoplasm; Blue = extracellular. The image on the lower right is a zoomed-out view of a portion of a plant cell (a pollen grain) - see how packed it is with structures!
Autophagy is part of the endomembrane system.
Discovery of autophagy and ATG proteins
Discovery of autophagy and ATG proteins
Autophagy was first discovered in the 1960s, the golden era of electron microscopy, by scientists who took electron micrographs of starved mammalian cells and observed the formation of autophagosomes. However, understanding a process biochemically requires knowing which proteins allow it to happen, and there was no progress on that front for over 30 years until scientists began applying the power of yeast genetics to discover genes necessary for autophagy. Screens in bakers yeast were carried out in the late 1990s by multiple labs, chief among them Yoshinori Ohsumi in Japan, Dan Klionsky in the US and Michael Thumm in Germany. (Yoshinori won a Nobel Prize in 2014 for his contributions to this field). These and subsequent screens identified the genes - and, thus, the proteins - that were necessary for autophagy in yeast, and further work soon showed that very similar proteins were involved in autophagy in all eukaryotes. Most of these are now known as "ATG" proteins (for AuTophaGy)
Images from Eskelinen et al. 2011, "Seeing is believing: The impact of electron microscopy on autophagy research" Autophagy 7:935 https://doi.org/10.4161/auto.7.9.15760
Also see Yang and Klionsky 2010 "Eaten alive: a history of macroautophagy" Nature Cell Biology 12:814 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3616322/
Top: Early electron micrograph (1962) of a mitochondria in an autophagosome in rat liver. Bottom: Freeze fracture EM image of a yeast cell with autophagic bodies in the vacuole
How does autophagy actually work?
How does autophagy actually work?
Knowing the proteins required to carry out the process of autophagy was a crucial first step, but just knowing the parts necessary to build a machine isn't the same as actually knowing how they all work and fit together. Many scientists around the world are working to understand how autophagy actually works and how it is controlled. Some are focusing on understanding the basic mechanisms using easy-to-study model organisms such as baker's yeast, while others are studying it in mice or rats to try to better understand the differences between autophagy in yeast and autophagy in humans.
Here's some of what we know so far about the machinery needed to build an autophagosome:
The Autophagy Initiation Complex gets the process started by recruiting the first few vesicles that fuse to make the beginnings of the autophagosome (called the phagophore). Part of this complex is a kinase, Atg1, that activates other autophagy proteins.
A PI3P kinase complex is recruited by Atg14 and creates the signaling lipid PI3P on the phagophore, which helps to bring in more Atg proteins.
Atg18, which binds to PI3P, and its partner Atg2, connect the growing phagophore to the ER membrane and transfer lipids from the ER to the phagophore to allow it to expand and begin wrapping up the cargo. Atg9, which was brought on the first vesicles, allows the lipid to flow between both sides of lipid bilayer.
A small protein called Atg8 gets attached to a lipid (PE) in the phagophore membrane, helping to attach the membrane to the cargo and playing other roles in its growth.
Once the phagophore has totally wrapped up the cargo, it seals into a mature double-membraned autophagosome and almost all of the Atg proteins leave, their job completed. Only some Atg8 stays on the inside of the membrane. Now, SNARE proteins allow the autophagosome to fuse with the lysosome/vacuole.
My research on autophagy
My research on autophagy
My research on autophagy has focused on three main topics:
Better understanding how Atg9 is directed to and from the site of autophagosome formation, and how its partners Atg23, Atg27 and Atg11 are involved. I did this work as a postdoc in the Klionsky lab.
Studying how Atg11 organizes the autophagy initiation complex during selective autophagy by making mutations in Atg11 that disrupt its interaction with other Atg proteins. This work has taken place at EMU.
Better understanding the roles played by various Atg proteins by determining whether modulating those proteins affects the size or number of autophagosomes, or both. I began working on this in collaboration with others while a postdoc in the Klionsky lab, and have continued it with different proteins at EMU. We are also working on improving the computational simulations necessary to estimate autophagosome size and number from electron micrographs.
You can learn more on my Current Projects page, or by reading my Publications.
This is an electron micrograph of a starved yeast cell that is unable to digest the autophagosomes that fuse with it's vacuole, causing them to build up inside. Images like this can be used to determine the size and number of autophagosomes formed.
The cleared-out space inside the cell is the vacuole, and the roundish objects clustered inside it are the autophagic bodies. Notice how they are filled with cytoplasm and pieces of the endomembrane system.
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