Cells are built to self-destruct

It sounds grim, but every cell in your body carries the tools to kill itself. That is not a design flaw. It is how your body removes cells that are damaged, worn out, infected or simply no longer needed, without leaving a mess.

This orderly self-destruction is called apoptosis. There are a few routes into it. The one this series cares about is called intrinsic apoptosis, and it is run largely through the mitochondria.

The BCL2 family

The paper explains that intrinsic apoptosis is tightly controlled by a group of proteins called the BCL2 family. Some members push the cell toward death. Others hold it back. The balance between them decides whether a stressed cell lives or dies.

BAX is one of the pro-death members. In the paper's words, it is a latent protein, meaning it is normally inactive, sitting mostly in the main fluid of the cell.

But it is not completely idle. BAX is in a state of balance with the outer surface of the mitochondria, drifting on and off. Protective proteins from the same family, like BCL-XL, keep shuttling it back into the cell fluid. In a healthy cell, BAX is kept away from where it could do harm.

What happens when the trigger is pulled

When a cell receives a strong enough death signal, that balance breaks.

Step one: recruitment. BAX moves onto the outer membrane of the mitochondria in large numbers.

Step two: assembly. Once there, BAX molecules pair up and then form larger clusters.

Step three: the leak. BAX makes the outer membrane of the mitochondria permeable. Scientists call this MOMP, mitochondrial outer membrane permeabilisation. It means the mitochondria spring a leak.

Step four: the alarm. Proteins that normally stay inside the mitochondria escape. The best-known is cytochrome c. Once cytochrome c is loose in the cell, it sets off a cascade of enzymes that dismantle the cell.

Step five: fragmentation. At the end of BAX recruitment, the mitochondria break up dramatically into small pieces.

How fast this happens

One of the most useful things in this paper is how precisely it describes the timing, based on earlier live-cell studies from the same lab.

  • BAX recruitment follows an S-shaped curve: slow start, rapid rise, then a plateau.
  • The whole recruitment phase takes about 20 to 30 minutes.
  • The leak and the release of cytochrome c happen almost instantly once recruitment starts, before the large BAX clusters form.
  • The mitochondria fragment once recruitment is complete.

That speed is important. Once BAX starts moving in earnest, the leak follows within minutes. That is why BAX is often described as a point of no return.

Why BAX is a tempting target

If you want to stop cells dying in an injury, BAX is an obvious place to look. Stop BAX gathering on the mitochondria and you stop the leak. Stop the leak and you stop the alarm. Stop the alarm and the cell survives.

That is why the brain bleed study we cover in another series was so interesting. It measured BAX in rat brain tissue and found that SS-31 reduced how much BAX ended up on the mitochondria after the bleed, and reduced how much cytochrome c escaped. The obvious reading was that SS-31 blocks BAX.

The question this paper asks

The Wisconsin team noticed something about how that brain study was done. It measured BAX in tissue at a single point in time, 24 hours after the injury, by separating mitochondria from the rest of the cell and comparing protein levels.

That is a perfectly reasonable method. But it is a snapshot. It cannot tell you whether SS-31 stopped BAX from moving, or delayed it, or slowed it, or just meant fewer cells had reached that stage by the time of the snapshot.

To answer that, you need to watch BAX move in real time, cell by cell. That is exactly what this lab is set up to do, and it is what the rest of this series is about.

The key idea to carry forward

If you remember one thing from this part, make it this: BAX moving onto mitochondria is fast, and the leak follows almost immediately. So if SS-31 truly blocks BAX, you should see it clearly in live cells. Either BAX would start later, move more slowly, gather less, or fail to cause the leak.

Next, we look at the unusual fat inside mitochondria that SS-31 binds to, and why the researchers thought it might connect SS-31 to BAX.

This series discusses a peer-reviewed laboratory study in cultured cells. The results have not been shown in people. Nothing here is medical advice, and SS-31 is discussed for research purposes only.