Why read them together
Over four separate series on this site, I have gone through four pieces of research on the same compound, a short mitochondria-targeted peptide called SS-31, also known as elamipretide.
Each series stands on its own. But reading one study at a time can give you a distorted picture. A single paper always looks either more impressive or more limited than it really is, depending on which paper you happen to pick up.
So this series does something different. It puts all four side by side and asks what they say together. Where do they agree? Where do they clash? What does the full picture look like, and what is still missing?
The four studies
Here they are in date order.
2011: Before the blood returns. A conference abstract from Weill Cornell Medical College in New York, with Hazel Szeto, one of the developers of the SS peptides, as a co-author. Mouse muscle cells in a dish were treated with SS-31 or hydrogen sulfide before three hours without oxygen. Both compounds roughly doubled a protective protein called HSP70 compared with untreated injured cells.
2020: The first seventy-two hours. A full paper from Hainan Medical University in China. Rats were given a controlled brain bleed, then SS-31 thirty minutes later. Treated rats had less brain swelling, a less leaky blood-brain barrier, fewer dying neurons, less oxidative damage and better behaviour scores at 24 hours.
2021: Sugar in the power plant. A full paper from Texas Tech University Health Sciences Center in the US. Diabetic mice were given SS-31 four times a week for four weeks. Their liver mitochondria showed less oxidative damage, more energy output, a better balance of splitting and merging, and stronger signals for building new mitochondria.
2021: The experiment that said not quite. A research note from the University of Wisconsin-Madison, partly funded by Stealth BioTherapeutics, the company developing elamipretide. Using live imaging of human cells, the team tested whether SS-31 blocks BAX, a protein that triggers cell death. It sped up mitochondrial recovery, but did not block BAX once the death process had started.
Four very different settings
What strikes me first, laying them out like this, is how different the settings are.
| Study | Tissue | Model | Problem |
|---|---|---|---|
| 2011 | Skeletal muscle | Mouse cells in a dish | Loss and return of oxygen |
| 2020 | Brain | Living rats | Sudden bleed |
| 2021 | Liver | Living mice | Long-term diabetes |
| 2021 | Retinal support cells | Human cells in a dish | Chemically triggered cell death |
Muscle, brain, liver, eye. Acute injury, chronic disease, oxygen loss, chemical stress. Dishes and living animals. China, New York, Texas, Wisconsin.
That range is part of what makes SS-31 interesting. Researchers in very different fields keep reaching for it because it targets something every one of those tissues relies on: the mitochondria.
The common thread
In every one of these studies, the core idea is the same. Mitochondria under stress leak harmful oxygen molecules, lose their ability to make energy and can push the cell toward self-destruction. SS-31 is designed to sit on the inner membrane of mitochondria and help keep them working.
Whether the stress comes from blood around the brain, years of high sugar, three hours without oxygen or a chemical trigger in a dish, the question is basically the same: if you protect the mitochondria, do the cells do better?
Three of the four studies say yes, on the measures they used. The fourth says yes to part of it and no to one popular explanation of why.
What this series will cover
Over the next seven parts:
- The mitochondria story from start to finish, using all four papers
- Where the four studies agree
- The one place they directly disagree
- The dose puzzle across rats, mice and dishes
- Why rats, mice and dishes still leave a gap where humans should be
- Who funded the work and who did it
- And finally, why "studied in rats" is not the same as "proven in you", and what to focus on first
If you have read the other four series, this one ties them together. If you have not, it gives you the whole picture in one place, and you can go back to the individual series for detail.
One thing to keep in mind throughout: none of these four studies tested SS-31 in people.
This series discusses four laboratory studies in animals and cultured cells. None tested SS-31 in people. Nothing here is medical advice, and SS-31 is discussed for research purposes only.
