Autophagy- tidying up, survival on a shoestring and death by over-cleansing

Autophagy literally means 'to eat oneself'. It is the cells way of recycling cytoplasmic components to give the cell a bit of a spring clean and get rid of any old or damaged proteins and organelles. As well as this homeostatic 'spring cleaning' role, autophagy can be upregulated in times of stress such as starvation to provide a source of amino acids. Autophagy can also act as a cell survival mechanism and a route to cell death depending on the circumstances. 

Mechanism of autophagy

Step one of autophagy consists of the formation of an isolation membrane, which sequesters the cytoplasmic component into a vesicle (autophagosome). This double-membraned vesicle then fuses with the lysosome, leading to the breakdown of the component and generation of amino acids (See Figure 1).

Key players in autophagy

mammalian Target Of Rapamycin (mTOR) - Induction

In stress conditions such as nutrient deprivation, mTOR acts as a sensor and initiates increased autophagy to generate much needed supplies. In nutrient rich conditions mTOR phosphorylates the autophagy factor Atg13, reducing its affinity to partner Atg1. Upon starvation, Atg13 can bind to Atg1 to begin the autophagic process.

Beclin-1 - Vesicle nucleation

Vesicle nucleation is triggered by the formation of a complex of Beclin-1, a phosphatylinositosol 3-kinase (Vsp15) and class III phosphoinositide 3-kinase (PI3K).

Microtubule-associated protein light chain 3 (LC3) - Elongation

Elongation of the autophagic membrane is supported by an Atg12-5 complex and LC3. LC3 locates to the membrane and is recycled upon vesicle formation via cleavage by Atg4.

Lysosomal-associated membrane protein (LAMP) -completion and fusion

In the final step of autophagy the fully formed vesicle fuses with the lysosome via interactions between LAMP and the GTPase Rab 7 and the contents are degraded and recycled.

Figure 1. Mechanism of autophagy

Autophagy steps include induction, vesicle nucleation, membrane elongation and completion and fusion

Autophagy and cell survival

When a cell faces death because of damage, the autophagy process can be used to try and dispose of the evidence before the apoptotic pathway is fully activated. If the apoptotic pathway begins, autophagy can be used to try to prevent further cell death by sequestering the activated mitochondria, preventing cytochrome c release into the cytoplasm.

Autophagic cell death

Due to the possible role of autophagy in cell survival, the role of autophagy as a death mechanism is controversial. Some hypothesise that autophagic vesicles are seen during cell death as a last ditch attempt to save a cell destined for apoptosis. Others suggest that when a cell cannot die via apoptosis, autophagy acts as a second death mechanism. By sequestering and degrading more and more cellular components, there comes a point where too many vital proteins and organelles have been degraded for the cell to continue and therefore it dies. Think of this like an over-zealous spring clean, in which you realise you have not only thrown away all your old stuff, you have also gotten rid of your phone, keys, laptop and passport.

Autophagic cell death theory was previously based the observation of autophagic vesicles and lack of apoptotic morphology. More solid scientific evidence has been observed in cells in which apoptosis was inhibited. Blocking Beclin-1 via RNA interference resulted in blocking cell death, suggesting autophagy was indeed responsible for death in cells not able to die by the more usual route of apoptosis. 

Autophagic cell death vs. apoptosis

So remember...autophagic cell death = cell spring cleaning gone a bit too far

To summarise:

Autophagy is a mechanism to remove and recycle old or damaged organelles.

Autophagy can induce cell death by degrading vital components so the cell can no longer survive. 

Autophagy can also be used as a survival mechanism to produce nutrients from organelles in times of stress.

Key proteins in autophagy are the Atg family of proteins, Beclin-1 and LC3.

References and extra info:

Autophagy in cell death: an innocent convict. Levine and Yuan 2005 J Clin Invest 115(10): 2679-2699

This article was really useful and covers the key points and contrversial nature of autophagic cell death

Other papers

Autophagy and cell death:no longer at odds. Bergmann 2007 Cell 131: 1032-33

 

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