Autophagy – why your cells eat parts of themselves to protect you from disease [Becky]

Our cells are self-cannibals.

You might have already heard of apoptosis, which in basic terms is cell suicide in times of crisis, when there is no more hope for a cell. But there are measures a cell can take before this. During starvation, and other crises such as infection, a process called autophagy kicks in, which is designed to digest large bits of cellular material.

This could be whole organelles such as mitochondria, or could even be a bacterium should it have invaded the cell. But what’s even more fascinating is that this process could potentially be manipulated to digest aggregated proteins, which are “misfolded” proteins that tend to clump together in cells, and are attributed to Alzheimer’s , Huntington’s, and Parkinson’s disease.

What is autophagy?

So first – let’s talk a bit more about what autophagy is. As well as being useful in times of cellular stress, it is a normal process that occurs on a regular basis inside healthy cells.

Dr. Christian de Duve, one of the founding fathers of modern cell biology. He discovered the lysosome (see text). Click for source
Dr. Christian de Duve, one of the founding fathers of modern cell biology. He discovered the lysosome (see text). Click for source

Like us, our cells generate a lot of waste. Molecules within our cells such as proteins have a turnover rate – they aren’t just static, but rather are broken down and re-made again in order to adapt to environmental changes.

Cells have their own personal waste disposal system, designed to digest old molecules. This happens in a couple of different ways. One method comes in the form of the lysosome, a compartment within our cells which contains various degrading enzymes, much like our stomach.

But far larger things than molecules are digested. The process responsible for this is called autophagy (quite literally from the Greek meaning “self-eating”). The term was coined in the 1960s by Dr. Christian de Duve, who discovered the lysosome, and is considered one of the founding fathers of modern day cell biology.

However, only in the last two decades has autophagy become a commonplace term at cell biology conferences. Writing in 2007, Daniel J. Klionsky, an expert in the field, stated that “Ten years ago, a seminar speaker who talked about autophagy could almost be guaranteed that no one in the audience, with the possible exception of the host, would have even heard of the term, let alone be familiar with any of the research”.

That has rapidly changed. Autophagy is crucial for cell survival, and is a complex process involving over 30 genes (rather imaginatively called ATG1, ATG2, ATG3, etc…). It is conserved in mammals, plants, some invertebrates and even slime mould (see here too if interested in slime mould), which indicates its importance.

How does it work?

Autophagy starts with the formation of a bit of membrane called a “phagophore”. Our cells are individually contained by a membrane, as are the organelles (such as the

Microscope image of autophagy in action. The green blobs are autophagosomes (see text). Click for source
Microscope image of autophagy in action. The green blobs are autophagosomes (see text). Click for source

mitochondria and the lysosome) inside the cell. The phagophore is made of the same building blocks as these membranes; however no one knows for certain where it comes from. Some believe it is derived from the existing organelles, or the cell membrane that surrounds the entire cell.

This phagophore then expands to engulf large bits of cellular debris, in the process becoming an “autophagosome”. This can then fuse with the lysosome we talked about earlier in order for the debris to be broken down. Think of the lysosome as the dustbin, and the autophagosome as the housekeeper tidying up large bits of rubbish.

What’s neat is that stuff can then be recycled. Products of lysosomal digestion can be brought out of the lysosome and can be used to build new organelles, or alternatively can be used in metabolic processes as an energy source (which means that autophagy can be very useful during starvation).

Autophagy can be messed up in disease, but might be a useful drug target

It has been found that autophagy is messed up in various diseases – for example it has been found to be inefficient in neurodegenerative diseases such as Huntington’s and Alzheimer’s disease. Autophagy also has a complex relationship with Cancer – in established tumours, autophagy may play a role in resistance to chemotherapy by assisting with the breakdown of drugs. However, autophagy may initially have a protective role against Cancer by protecting against metabolic stress and therefore reducing DNA damage that can lead to tumour formation.

However, knowing this means that we might be able to intervene therapeutically. David Rubinsztein’s laboratory have shown that drugs can be used to induce autophagy and aid in the clearance of the toxic proteins seen in Huntington’s Disease, and that they can have protective effects in various animal models of the disease.

HIV particles assembled on the surface of a white blood cell. Click for source.
HIV particles assembled on the surface of a white blood cell. Click for source.

Manipulating autophagy may have uses for other diseases too – Autophagy normally helps in the clearance of bacteria and viruses, but it can be helped along. Vitamin D has been shown to inhibit replication of HIV and Mycobacterium tuberculosis (a pathogen responsible for tuberculosis) in human white blood cells, through an autophagy-dependent method.

So autophagy is a crucial process for the survival of our cells, and also plays many protective roles, such as protection against neurodegenerative diseases, pathogens and cancer. What’s more, we may be able to manipulate it to treat disease, though this is likely to be complex considering the importance of autophagy in cell housekeeping. I think you will agree this is a fascinating and exciting area of research.

Dr. Christian de Duve won the Nobel Prize in Physiology and Medicine in 1974.

Sources

Choi et al. (2013) Autophagy in Human Health and Disease. The New England Journal of Medicine. 368:651-662.

Glick et al. (2010) Autophagy: cellular and molecular mechanisms.  Journal of Pathology 221: 3-12.

Klionsky (2007) Autophagy: from phenomenology to molecular understanding in less than a decade. Nature Reviews Molecular Cell Biology 8(11):931-7

Rubinsztein et al. (2012) Autophagy modulation as a potential therapeutic target for diverse diseases. Nature Reviews Drug Discovery 11(9):709-30

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