Bad, And Why Switching It Off Helps

A protein that lives up to its name

Some proteins have dull names made of letters and numbers. This one is called Bad, and for once the name fits.

Bad is one of the proteins that push a cell toward self-destruction, the orderly kind of cell death called apoptosis. It belongs to the same BCL2 family as BAX, the protein at the centre of our Wisconsin series. Members of this family either push toward death or hold it back, and the balance decides the cell's fate.

Bad is a pusher.

How Bad works

Bad does not kill the cell directly. It works by interfering with the proteins that keep the cell alive.

Protective proteins in the BCL2 family hold back the death machinery at the mitochondria. Bad binds to those protective proteins and ties them up. With the protectors tied up, the death machinery is free to act, and the cell moves toward apoptosis.

So active Bad is a threat. It disarms the cell's defenders.

The off switch

Cells have a way of switching Bad off. They attach a small chemical tag, a phosphate group, to it. This process is called phosphorylation.

When Bad is phosphorylated, it changes behaviour. As the abstract explains, phosphorylated Bad is an inactivated form of the normally pro-apoptotic Bad that has been sequestered in the cytoplasm. In plain terms, the tagged Bad is held away from the mitochondria, in the main fluid of the cell, where it cannot interfere with the protective proteins.

So more phosphorylated Bad means more Bad has been switched off and locked away. That is good for cell survival.

What the study found

The team measured phosphorylated Bad after three hours without oxygen and 24 hours of recovery.

For hydrogen sulfide, the abstract reports these relative levels:

A few things jump out:

• Hydrogen sulfide raised switched-off Bad in both conditions, with and without the injury.
• After the injury, untreated cells had the lowest level of switched-off Bad of any group, 0.44. The injury left more Bad active.
• Hydrogen sulfide treated cells after the injury had more than double that, 0.96.

The comparison between hydrogen sulfide treated and untreated cells after anoxia was statistically significant, with a reported p-value of 0.038.

And SS-31?

Here is the honest part. The abstract does not report a significant effect of SS-31 on phosphorylated Bad. Its conclusion states the phospho-Bad increase for hydrogen sulfide only. It does not give the SS-31 phospho-Bad numbers at all.

We should not assume SS-31 did nothing to Bad. Maybe its effect was smaller, or more variable, or did not reach significance. Maybe it acts on a different part of the pathway. The abstract simply does not tell us.

What it does tell us is that, in this experiment, switching off Bad was clearly linked to hydrogen sulfide, while both compounds shared the big rise in HSP70 from Part 5.

Why the difference is interesting

That split is actually one of the more informative findings in the abstract.

Hydrogen sulfide is a signalling molecule. Signalling molecules often work by changing which proteins get tagged with phosphate groups. So it makes sense that hydrogen sulfide would show a clear effect on phosphorylated Bad.

SS-31 is thought to work mainly by protecting the mitochondria physically, sitting on the inner membrane and supporting its structure. That is a different kind of action. It would not necessarily involve tagging Bad.

So the results fit what you would expect from how each compound works. Both raised the cell's repair crew. Only the signalling gas clearly switched off this particular death protein.

Connecting to the other series

This fits neatly with what we learned from the Wisconsin study. There, SS-31 did not stop BAX, another BCL2 family death protein, once the death process had started. Here, SS-31 was not reported to switch off Bad.

Taken together, the evidence across these papers suggests SS-31 is not mainly a direct blocker of the BCL2 death proteins. Its strengths seem to lie elsewhere: supporting mitochondria and helping the cell build up its own defences, like HSP70.

That is not a weakness. It is useful information. It tells you what kind of tool SS-31 is, and what kind it is not.

The bottom line on Bad

Hydrogen sulfide switched off a death protein in muscle cells after a simulated injury. SS-31 was not reported to do so. Both strengthened the cell's repair machinery.

Next, we look at a number in this study that is easy to skip and should not be: how little SS-31 the team actually used.

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