Repair is one thing, renewal is another
In Part 4 we looked at how mitochondria split and merge. That is about managing the mitochondria a cell already has.
But cells can also build new mitochondria. This is called mitochondrial biogenesis, and it is one of the main ways a cell adapts to how much energy it needs. It is also, as it turns out, one of the things that suffers in diabetes.
The chain of command
Biogenesis is controlled by a small set of proteins that work like a chain of command. The paper measured four of them.
PGC-1α is the master switch. When it is switched on, it sets the whole process in motion. The paper notes earlier research showing that PGC-1α increases the capacity of mitochondria for many metabolic processes.
Nrf1 and Nrf2 (nuclear respiratory factors 1 and 2) are its deputies. PGC-1α works with them to turn on the genes needed to build the mitochondrial energy chain.
TFAM (mitochondrial transcription factor A) works inside the mitochondria themselves. Mitochondria carry their own small piece of DNA, and TFAM is needed to copy and read it. Without enough TFAM, new mitochondria cannot be properly assembled.
So you can think of it like building a factory. PGC-1α gives the order. Nrf1 and Nrf2 bring in the materials. TFAM runs the assembly line inside the building.
What diabetes did
In the livers of diabetic TH mice, all four of these proteins were lower than in healthy controls. The drop was statistically significant for Nrf1 and TFAM.
The authors read this as impaired mitochondrial biogenesis in the diabetic liver. Fewer orders, fewer materials, a slower assembly line. Fewer new power plants being built at the very time the existing ones are being damaged by high sugar.
That is a bad combination. If damaged mitochondria are being cleared out by fission (Part 4) but not replaced by biogenesis, the cell gradually runs short of working energy machinery. That would fit the low ATP levels we saw in Part 3.
What SS-31 did
This was one of the strongest results in the paper.
At the gene level, compared with untreated diabetic mice, SS-31 increased:
- PGC-1α by about 2.6-fold
- Nrf1 by about 2.2-fold
- Nrf2 by about 1.9-fold
- TFAM by about 2.2-fold
The PGC-1α and Nrf1 increases had the strongest statistical support in the gene data.
At the protein level, all four went up significantly in SS-31 treated mice compared with untreated diabetic mice.
The authors' conclusion is direct: SS-31 enhanced mitochondrial biogenesis in the livers of diabetic mice.
Why this result stands out
Most of what SS-31 is known for is protection. It settles on the inner membrane of mitochondria and is thought to reduce the damage from oxygen radicals. That is defensive.
This result is different. More PGC-1α, more Nrf1 and Nrf2, more TFAM points toward the cell building new mitochondria, not just protecting old ones.
The paper does not prove exactly why SS-31 has this effect. One reasonable reading is that once the existing mitochondria are working better and leaking less, the cell's normal signals to grow new ones can work again. Another is that SS-31 has more direct effects on those signals. The study is not designed to separate those.
Either way, the result is that the diabetic liver moved from "fewer new mitochondria" back toward normal.
The bigger lesson about mitochondria
There is a broader point here that applies well beyond SS-31.
Mitochondrial biogenesis is something the body already does on its own in response to the right signals. Regular exercise is one of the best-studied ways to switch on PGC-1α in muscle. That is a big part of why trained muscles have more mitochondria and use energy more efficiently.
So when a study finds that diabetes suppresses this system, it is a reminder that it is a system you can influence. A compound might do it in a mouse. Your daily habits definitely do it in you.
A careful note
This was measured in the liver of male mice, after four weeks of treatment, with six mice per group. It is a clear and consistent result within those limits. It is not evidence that SS-31 builds new mitochondria in people.
Next, we look at what the liver tissue itself looked like under the microscope, and what changed with SS-31.
This series discusses a peer-reviewed laboratory study in mice. The results have not been shown in people. Nothing here is medical advice, and SS-31 is discussed for research purposes only.
