Transcription
The study I'll be showing you hasn't even been published yet. I'll explain what that means in a bit, but the data shared by the researchers will be cutting edge in respect to mitochondrial health and function and its relationship to an amino acid. It's the first ever described mechanism of its kind, and it'll likely make waves. But what are we talking about here? I'm talking about this study.
Now, to be clear, this is not peer-reviewed. This has been uploaded pre-publishing to bioRxiv, a pre-publishing site to post studies before a journal publishes it with peer review. I'm sure that the full study won't deviate much from what I'll be showing you here, but if there are any significant changes, I'll update you. That said, the data within is fascinating because it tells us three things:
1. A new mechanism by which exercise improves mitochondrial function.
2. The relationship between improved mitochondrial function and a specific amino acid.
3. What impact supplementing with this amino acid might have on mitochondrial function independent of exercise.
It tells us one more thing: something that has to be present for the amino acid to work. But let's break this down, and then I'll put it all together for you in a neat package at the end.
First, the researchers wanted to know which metabolites—molecules—are more or less present between mitochondria that have been involved in exercise and those that haven't, so sedentary. The researchers can quantify the amount of metabolite in exercise mitochondria and sedentary mitochondria, looking at which metabolites are in the extremes, indicating significant difference and a likely target for discovering exercise's benefits.
We can see that here. This is a volcano plot of an experiment called targeted metabolomics. The higher the dot, the greater the difference in its concentration between exercise and sedentary mitochondria. As you can plainly see, they identified the amino acid ergothioneine, and we can see that further quantified here, with the red bar indicating increased ergothioneine concentrations in exercised muscle.
As an aside, have you ever wondered how they isolate mitochondria from cells? I actually have a lot of experience with this because I've done it in the lab myself. However, the researchers did something a bit more refined than what I've done. They had mice with what's known as a triple-H tag applied to mitochondria, so all the mitochondria have this tag on them, which allows the researchers to capture mitochondria that have this tag through an experiment called immunoprecipitation.
Anyway, this is how they isolate mitochondria to run experiments on them specifically. So they had a group of sedentary mice and exercising mice that express these tagged mitochondria and then simply did what I just described to capture the mitochondria and run experiments that we'll go over now.
They've identified the amino acid ergothioneine, and the next question is: what is the relationship of ergothioneine to mitochondrial function? For that, the researchers plated muscle cells in a dish and applied ergothioneine to the cells or a control called the vehicle that does not have ergothioneine. Then they measured the oxygen consumption of the cell.
So why oxygen consumption? Well, if you've seen other Physionic videos, you might already know, but mitochondria utilize oxygen when functioning to generate cellular energy. So the greater the oxygen consumption, the greater the mitochondrial function. It acts as a close proxy measure.
And what did they find? Well, they discovered that when they added the ergothioneine, the mitochondrial function increased, as evidenced here. This is called a Seahorse assay, which is actually another experiment that I've had the pleasure of learning in my PhD. I'll just mention that if the reddish lines and bars are higher than the black lines and bars, that indicates an increased oxygen consumption by mitochondria in the ergothioneine-exposed cells. In multiple measures, there is such an effect indicating a direct effect of ergothioneine.
However, one of the mysteries of ergothioneine is that, well, no one knows how it fulfills this role. I mean, we understand that it has a positive effect on mitochondrial function, but how? And also, can we supplement it to see this effect? We'll get to that question too.
First, let's describe how ergothioneine has this effect. Remember, it's completely unknown how ergothioneine has this effect. So how can the researchers probe this question? Well, similarly to how they discovered ergothioneine, they started looking at which molecule is highly divergent between ergothioneine-supplemented and nonsupplemented muscle cells. For this, however, instead of metabolomics, they did proteomics, which identifies proteins, and they land on MPST.
MPST, or 3-mercapto-pyruvate sulfur transferase, is an enzyme found inside the mitochondria. Okay, so they knew it was highly enriched in ergothioneine-exposed mitochondria, and we can see that further evidenced here, as greater ergothioneine concentrations are applied, MPST levels rise. Remember, the vehicle is a control condition, so no ergothioneine addition.
Then they show a molecular model of the MPST protein, so the enzyme, and identify that ergothioneine would fit in it. As in, it would be able to attach—a little tough to see, but they're zooming into a pocket of the MPST protein and showing that the ergothioneine amino acid does fit.
Okay, all well and good, but all of that doesn't prove that MPST is the actual mechanism of action. All that we know is that ergothioneine increases its prevalence and seems to bind to it, but that doesn't speak to the functional outcomes. So what happens when we inhibit MPST and repeat the exposure of ergothioneine to mitochondria? Are they still active, indicating that MPST has no effect, or are they inhibited, indicating that this is a mechanism of action?
Well, we can turn to the data like brave little scientists that could. On top, we see the mitochondrial function in cells with functioning MPST. Again, the red lines and bars are ergothioneine-supplemented. The bottom graph is the exact same experiment, but after the cells have also been exposed to an inhibitor of MPST called I3MT. Such a sexy name! The blue is the ergothioneine-exposed mitochondria.
Notice anything? That's right! When the inhibitor is not present, we still see the improvement in mitochondrial function, but we lose that improvement when MPST is inhibited, although ergothioneine is still present. This strongly indicates that ergothioneine confers mitochondrial benefit through the MPST enzyme.
But what does it actually do? Aren't you the least bit curious? If you have the mind of a scientist, you're intrigued. So allow me to touch on this, and then I promise that we'll get to the supplementation and how this applies to humans.
MPST, which I refuse to mention the full name again because I barely survived the first time, is an enzyme that adds sulfide molecules to functional proteins within the cell, especially in mitochondria. This process of sulfide tagging to proteins is called persulfidation, and it changes the function of the proteins. Not only that, this enzyme can help produce a molecule called pyruvate, which is a common precursor to energy generation by mitochondria. I won't go into the specifics now, though, so it can directly influence the activity of multiple mitochondrial proteins and can add to the pool of precursor molecules for cellular energy generation.
It's believed, although unconfirmed yet, that ergothioneine may either deliver more hydrogen sulfides to the MPST or it may bind to the MPST and regulate its activity through what is called allosteric regulation, which simply means that the binding leads to changes in activity. So I'd like to return to this in a bit because there are a few more tidbits that I really find fascinating, but currently, not all the answers are known. However, we are at least in some know of the activity of MPST.
Okay, now we know exercise increases ergothioneine in the mitochondria, and we know that it acts through MPST to increase mitochondrial function. However, what if we bypass exercise and simply eat more ergothioneine? Does that work too? Naturally, the researchers added ergothioneine to the food of mice, and instead of measuring mitochondrial function, they aimed for something better: actual physical function.
Here are the results: the control diet is the mice that are fed the same food minus ergothioneine, and the ergothioneine diet is, well, I think you get it. Here, we're measuring the speed of exercise, so the peak activity, and we see that the ergothioneine group outperformed the control group. What's really remarkable here is the effect wasn't small either—almost 30% better performance.
So I won't bog this down with more data, although there is more. For example, the researchers repeated this experiment in mice deficient in the MPST enzyme, and well, guess what happened? Exactly what you would expect: no benefit of ergothioneine supplementation.
So where does that leave us? We now know that ergothioneine is implicated in improved mitochondrial function through an MPST-dependent pathway. We also know that exercise increases mitochondrial ergothioneine. Fascinatingly, the researchers took previous data of blood levels of ergothioneine in humans and showed that exercise, endurance, and resistance training increase blood ergothioneine in humans.
Additionally, something to add here: exercise actually also increases MPST expression as well as the localization of MPST to the mitochondria, which is also really fascinating. Also, I didn't report this data, but the researchers also showed an effect of exercise on the ERG transporter, the protein that allows ergothioneine into the cell through a mitochondria-centric mechanism. So I left that out because it's complex enough, although I may cover it in future work.
Finally, we have some indication that supplementing with ergothioneine can provide these benefits as well. Now, we need to be cautious and point out that this is using an animal model, which certainly has its advantages and disadvantages. I would absolutely like to see this repeated in humans, and it should be relatively easy to do so since we're talking about muscle mitochondria, which are much easier to access than something like your liver or your brain.
But as it stands, only preliminary evidence points to the amino acid ergothioneine being a potent target for supplementation leading to improved mitochondrial function. Let's see where future research takes us, like this research right here, which I think you'll find equally fascinating. Speak with you over there. [Music]