Biological Jenga: Autophagy and Cell Death

As you may have guessed from previous posts, I’m intrigued by architecture and buildings. I’ve also found that construction and buildings can be fertile grounds for metaphors of biology, such as when I wrote about imploding buildings and caspases. But as a scientist, I don’t lay bricks or pour foundations every day, nor do I swing a wrecking ball or wire buildings with explosives for demolition. So, I’m quite removed from the world of architecture and construction.

But I do have hands-on experience with a simpler type of construction: I’ve played Jenga. And I’m guessing that you have also experienced building towering structures of wooden blocks, carefully moving blocks from lower levels to the top to keep pushing the structure skyward. While repurposing the lower blocks to the top can help grow the tower’s height, if you pull too many blocks, the base becomes too weak, and the structure collapses.

There is a similar process that occurs in our cells, a biological Jenga, of sorts. It’s called autophagy. In Jenga, we repurpose lower blocks to push the tower higher. In our cells, autophagy allows them to repurpose some of their internal components to further their own survival. But if cells rely on autophagy for too long, they can trigger their own demise, just like when the Jenga tower crashes down because too many of the lower blocks have been removed. 

With its Greek roots, the word “autophagy” roughly translates to “self-eating,” an appropriate description of the process. Autophagy is a way for the cell to degrade its own cellular contents, recycling them into building blocks that can be used to construct new things. For example, less essential proteins can be broken down during autophagy into their amino acid subunits, which can then be reused to make new, more essential proteins.  

While many cells maintain low baseline levels of autophagy, the process really kicks into gear in response to cellular stress. Nutrient starvation and growth signal withdrawal are common stressors that can induce cellular autophagy. Without a stream of nutrients and other growth signals, the cell no longer has its source of building blocks for protein production, energy generation, and a variety of other fundamental processes. As you can imagine, if the cell is starved of the things it needs to survive, it’s going to die. But autophagy provides a way for the cell to generate an alternative source of those building blocks so that it can keep those key functions going. When done right, autophagy can keep cells alive until their normal nutrient stream is restored.

So how does autophagy work?

When a stress signal is detected, a signaling cascade is triggered within the cell, leading to the formation of a structure called the autophagosome through the involvement of a number of proteins, including Beclin-1, Vps34, LC3, Atg5, Atg12, and Atg16. The autophagosome is a membrane structure that is formed around a relatively nondiscriminatory area within the cell, enveloping whatever cell components are in that area (proteins, organelles, etc.). This is similar to a net being cast over a school of fish in the ocean, trapping whatever fish end up encircled by the net.

The autophagosome, once completely formed, and its entrapped cellular components begin to merge with another cell structure called the lysosome. This structure is a membrane structure like the autophagosome, but its contents are acidic and include a host of degradative enzymes. Like two soap bubbles merging to create one big bubble, the autophagosome and the lysosome combine to create the autolysosome. This event releases the lysosome’s enzymes into the autophagosome, where the enzymes act like molecular scissors and cut up the entrapped proteins and organelles into their requisite subunits. The resulting amino acids and simpler compounds can then be used by the cell to produce new proteins and structures vital for cell survival.

But, as you know, a Jenga tower that is too tall eventually collapses because its base is too weak, and a cell that relies too much on autophagy will eventually trigger its own death.

Autophagy is associated with a number of cell death mechanisms, triggered by separate means. These can be broadly characterized into two different relationships: one where autophagy can help activate other cell death signaling cascades, and another where autophagy itself is lethal.

In the former case, there are three general ways that autophagy can help encourage the propagation of cell death signals. First, if the autophagy pathway is blocked, it can trigger cell death signaling. For example, if autophagy is activated, but the autophagosomes are blocked from merging with the lysosomes, autophagy can be shunted toward apoptosis and necroptosis.

Second, the autophagy process can envelop and destroy key proteins needed for cell survival and inhibition of cell death signaling. Researchers have shown that in certain conditions, autophagy can consume and destroy a protein called PTPN13 (also called FAP-1), which is an inhibitor of the death signaling triggered by the cell surface receptor Fas. In the absence of the inhibitor, Fas is free to trigger apoptotic cell death. Autophagy has also been shown to degrade the IAP family of proteins, key regulators of cell death and survival signaling. In their absence following autophagy, cells can exhibit necroptotic cell death.

Third, autophagy can promote cell death through a mechanism that is independent of its consumption of cellular contents, unlike the previous examples discussed above. In this case, rather than focusing on the content of the autophagosomes, the attention is on the autophagosomes, themselves. In this context, they act as scaffolds for additional signaling complexes that propagate cell death. Proteins that normally form the death-inducing signaling complex (DISC) on surface receptors like Fas can instead bind to the autophagosome, leading to an intracellular activation of caspase 8 and the subsequent cell death cascades.

While autophagy can help activate well-established cell death pathways, it can also be the direct cause of a cell’s death.

In one instance, the cell can essentially eat itself to death. This is the classic Jenga example where the cell has turned on too much autophagy and overconsumed its own contents. This essentially hollows out its base and leaves it too weak to survive. This eventually leads to the breakdown of the cell’s membranes and the death of the cell.

There is another form of excessive autophagy that leads to the cell’s demise. In this case, though, it’s a special type of autophagy, one that focuses on the mitochondria and is a process called mitophagy. As you may remember from cell biology, the mitochondria are the power plants of the cell and are vitally responsible for the cell’s energy production. Mitophagy is the application of the autophagic process to the consumption and destruction of mitochondria. Like autophagy in general, mitophagy is often a good thing, as it’s used to remove damaged or malfunctioning mitochondria. But under certain conditions, mitophagy can become overactive, leading to the overconsumption of the cell’s mitochondria, depleting the cell of energy and essentially pulling the plug on the cell.

A third form of autophagy-dependent cell death is called autosis, which can be triggered by high doses of cell-permeable peptides to trigger elevated levels of autophagy. In autosis, there is initially an accumulation of autophagosomes and autolysosomes. Eventually, abnormal mitochondria are observed, and various membrane structures begin to disintegrate, leading to the eventual rupture of the cell’s outer membrane. It’s believed that death by autosis is associated with disruption of the careful balance of ions – such as sodium and potassium ions – throughout the cell. Because this balance is critical to maintaining the proper compartmentalization of water in the cell, any imbalance can lead to an influx of water followed by cellular swelling and rupture.

While autophagy is associated with cell death and may appear to be dangerous, it does provide valuable survival mechanisms for our cells. Just like Jenga, it’s a careful balancing act between success and demise.

This post was inspired and informed by: Bialik S, Dasari SK, Kimchi A. Autophagy-dependent cell death – where, how, and why a cell eats itself to death. J. Cell Sci. 2018. 131, doi:10.1242/jcs.215152.

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