The Biggest Myth About Mitochondrial Health

0:00What if your cells are getting more fuel than they can handle? Your mitochondria are the parts of your cell that turn food into energy. But when too much fuel is coming in at once, especially glucose and fat, your mitochondria can struggle to keep up. That's something we see with insulin resistance and type 2 diabetes. And it may explain why simply adding supplements or other mitochondrial boosters isn't always the answer. Two things appear to matter most. Exercise helps your body build more mitochondria, giving you more capacity to burn fuel. And lowering the amount of fuel coming in, especially by keeping insulin and blood sugar under better control, helps keep those mitochondria from getting overwhelmed.

0:45So improving mitochondrial health may be less about finding the newest supplement and more about helping your body handle fuel better. This is Lecture 160 of The Metabolic Classroom. With no fees or minimums on checking accounts, it's no wonder the Capital One bank guy is so passionate about banking with Capital One. If he were here, he wouldn't just tell you about no fees or minimums. He'd also talk about how most Capital One cafes are open seven days a week to assist with your banking needs. Yep, even on weekends, it's pretty much all he talks about. In a good way. What's in your wallet? Terms apply.

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3:26Welcome to the Metabolic Classroom. I'm Ben Bickman, metabolic scientist and professor of cell biology. Mitochondria are having a moment. Health influencers describe them as the root of nearly every chronic condition. Peptide manufacturers, of course, are marketing compounds aimed at improving mitochondrial function. And of course, we have the longstanding influences and involvement with pharmaceutical companies. It's justifiable. Of course, in this case, they're developing drugs for mitochondrial disease and for the mitochondrial component of conditions like heart failure and neurodegeneration.

4:05So a very justifiable role from them in this case. Some of this attention is warranted and effective because these organelles sit at the center of how a cell handles fuel. how it handles oxidative stress, and much more. What's largely absent from the conversation is measurement. The tests that quantify mitochondrial function are built to diagnose very rare inherited diseases, and almost nobody outside that setting is running them on ordinary people. You wouldn't need to. But that does mean that there is a large open space, and it has filled with interventions and some data, including some supplements and things like methylene blue or uroliothin A or red light or cold exposure.

4:55All of these things are things we will discuss at the end because there is some evidence to support them. All right, let's get started as usual with the foundational ideas in this mini lecture. Mitochondria, and just as a point here, mitochondria ending with an A is a plural word. So that is the plural form of the term mitochondrion, O-N. So there's an individual mitochondrion, but all together within the cell, we just call them collectively the mitochondria. So if you ever hear the word mitochondria used plural form, then someone's using it correctly, which I'm going to today. Case in point, mitochondria are compartments inside our cells.

5:40Every cell except one, I wonder if you can guess it before I tell you, it's the red blood cell. Every cell except your red blood cells have mitochondria in them. I won't get into the reasons why for the red blood cells, but within the cells that have mitochondria, their primary job is to convert the chemical energy stored in food. When you think about calories in food or calories stored in fat cells, but it converts that chemical energy into a form of energy that the cell can spend, or in other words, can use to get something done. Most of it we'll discuss in this mini lecture depends on how that conversion works.

6:20So I want to talk about that first. Let's just start with glucose. When a cell takes in glucose, the first stage of breakdown actually happens outside the mitochondria. In the cell though, but outside the mitochondria, and it is in this watery fluid compartment of the cell called the cytosol. That process is glycolysis, and it will split one six-carbon glucose molecule into two three-carbon molecules of pyruvate. That's what it's going to get to at the end of glycolysis. Now, the journey's not over yet. Now, during this process, that process of glycolysis, getting from glucose to pyruvate, that will yield a little bit of energy.

7:05It yields a little bit of this energetic molecule called ATP, and we're going to talk more about that later. But it does so without requiring or using any oxygen. All right, that's another point we're going to come to in a moment. Now, as I noted, the journey isn't over with getting to pyruvate. Pyruvate is then carried into the mitochondrion and converted into a two-carbon molecule called acetyl-CoA. Interestingly, when we burn fat, it actually reaches the same destination. So if you think about fat burning, you also are breaking down the fat into acetyl-CoA. But of course, it's starting with a different origin.

7:47So it's coming to acetyl-CoA from a different place. Fats will enter the mitochondria and are cut down two carbons at a time through a process called beta oxidation. When you think about fat burning, that's actually, this is what you should be thinking about, the beta oxidation, the breaking down. But each of those two carbon molecules that are coming off of that long chain of carbons that we call a fat molecule, each of those is acetyl-CoA. That's not all. even beta-hydroxybutyrate, the main ketone, will also get metabolized into acetyl-CoA, and that's how it also gives energy. So carbohydrate, fat, ketone, they arrive by separate paths, but they converge on the same molecule, acetyl-CoA, inside that same compartment, the mitochondria.

8:35And this convergence is the reason the two or even three fuels, mostly two, just fats and glucose, can compete with each other. Now, acetyl-CoA, the journey's not over yet. It feeds into the famous Krebs cycle or the citrate cycle or the strict acid cycle. It's all the same thing. That cycle is usually described as producing energy, but what it mainly does is strip electrons off of the fuel, and then it loads those electrons onto carrier molecules, The most famous of which, and most important, is NAD. That is the same molecule at the center of all of these NAD-boosting supplements, that whole supplement category of NR and NMN.

9:18All of those are an attempt to increase NAD within the cell. When NAD picks up electrons, it becomes NADH, and NADH is essentially a delivery vehicle carrying those electrons to the next stage in this fuel-burning process. Now that next stage happens on what's called the inner mitochondrial membrane. So the mitochondria has two membranes, an outer membrane and inner. All of this action that we're going to be talking about with mitochondrial function is on the inner mitochondrial membrane. Embedded in that membrane is a series of very large protein complexes. And electrons are basically shuttled or handled from one complex to the next.

10:01in generally in a sequence. It's not a perfect one, two, three, four, but close enough. People often call it the electron transport chain or the respiratory chain. I prefer the term electron transport system or the respiratory system regardless. And I won't get into the reasons why all of these names refer to the same thing, the same structure or structures. And I'm going to use them pretty interchangeably over the course of this mini lecture because the literature uses these terms interchangeably. Now, at the end of that electron transport system, we come to a very important molecule called oxygen.

10:40Oxygen accepts those electrons. So remember, those big protein complexes are passing the electrons kind of down the line. And then eventually it gets to the end and oxygen is there waiting. And when oxygen takes on that electron, it also takes on a hydrogen. And when you think about hydrogen and oxygen, what are you thinking? You're thinking H2O. You're thinking water. This is metabolic water. That's the end product. This is, you could say, why we breathe. Every breath you take exists to deliver oxygen to the far end of this system so that electrons have somewhere to go. And this fact has a very practical consequence that runs through the rest of the episode as we will get into.

11:26Because oxygen is consumed or used up at the end of that respiratory system in proportion to how many electrons are moving through it, we scientists are able to measure how much oxygen a tissue consumes. We can measure how much oxygen the mitochondria are using, and that gives us an idea of how much the mitochondria are working. Nearly every technique I'm going to describe later is some version of measuring oxygen consumption. In fact, and indeed, even in my own lab, as I'm going to share some results from my lab in just a bit. Measuring mitochondrial respiration is a workhorse tool in my lab.

12:07Ultimately, moving electrons down the system releases energy, and the mitochondria use that energy to make ATP. That's the molecule that the cells will spend to do virtually anything you want that cell to do. You want a muscle to contract, you need some ATP. You want to send a nerve impulse to think or to react or do anything, that's more ATP. Every action any cell is doing is being bought or purchased by the cell using up some ATP. Now, there is a couple of follow-up points worth making as I kind of near the end of this foundational idea in the mini lecture. The first is that the link between fuel burned and ATP produced is not fixed.

12:56Mitochondria can burn fuel and use oxygen without producing much ATP. So it ends up spending that burned fuel as heat instead. When most of the fuel ends up as ATP, we call it coupling. So the breaking down of the energy is tightly coupled or results in a high production of ATP. When a lot of that breaking down of energy comes off as heat, but not ATP, that's uncoupling. Now, neither is automatically good or bad. Uncoupling is what brown fat does, and it does it on purpose to generate heat. Now, that's another concept we're going to revisit in a bit as we touch on some of what my lab has done to help you understand more of this topic overall of mitochondrial function.

13:44All right. Now, the second feature is that the system, the mitochondrial system, the electron transport system is imperfect. A small fraction of the electrons that are being passed from one protein complex to the other escape before reaching oxygen at the end and these react prematurely with oxygen to form reactive oxygen species ros including the most famous perhaps or the most relevant which is hydrogen peroxide at low levels hydrogen peroxide is used as a signal of this oxidative stress status at high levels um we can still measure it but that this is where it starts to become very damaging now you're thinking of hydrogen peroxide as something you put on your wound that's right but imagine that same process of scrubbing away your skin happening within your cell that's not good um where the at high levels the hydrogen peroxide is damaging anything it comes in contact with.

14:45It's damaging proteins, membranes, DNA, and how much an individual mitochondrion emits per unit of oxygen consumed is a reasonable index of how cleanly the mitochondria are running. In other words, you can look at the amount of hydrogen peroxide being produced based on how much oxygen the mitochondria are using, and that gives you a pretty good idea of the status of oxidative stress. One final bit of introductory information is that mitochondria are not fixed structures just sitting there. They continuously divide and fuse with one another. So what a cell holds by way of mitochondria is really less a collection of separate units than it is a shifting network of these units.

15:32And the balance between division and fusion or fission and fusion determines how connected the network is. That's a process called, that overall concept is referred to as mitochondrial morphology or dynamics. Okay, this has all been background. Now let's get into some of why the mitochondria may matter in metabolic contexts, specifically disease. So with this in mind, let's talk about insulin resistance and type 2 diabetes, these two extremely common disorders. And of course, insulin resistance being the ultimate measurement of metabolic health. Evidence consistently shows reduced mitochondrial capacity in muscle from people with type 2 diabetes.

16:16Muscle biopsies from the thigh, so the big muscles of your upper leg, show that the respiratory system activity is highest in lean individuals who are insulin sensitive. It's a little lower in those who are obese, but still reasonably insulin sensitive. And it is the lowest of all in those with full-blown type 2 diabetes. Interestingly, if you zoom into the cell and take pictures of the mitochondria through what's called electron microscopy, these same studies have found that the mitochondria are roughly a third smaller in both the obese and diabetic groups when compared with the lean group. a separate line of evidence actually looked at these subpopulations of mitochondria and looking at where they were found within the cell, within the muscle cell.

17:09And they found that it was particularly the mitochondria in what's called the sub-sarcolemmal space. That's the space just beneath the membrane or the wall of the muscle cell. That was significantly down. In fact, it was reduced to about one-seventh the level in the diabetic group compared with the lean insulin-sensitive group. So a significant reduction specifically in the function of those mitochondria, which interestingly are the mitochondria that are primarily involved in burning fuel. Now, how you measure mitochondria matters here. I'd noted before oxygen consumption or the rate at which the cell or the mitochondria is using up oxygen within the muscle, it really reflects the capacity of the entire tissue.

17:59Now, that's not the same as measuring oxygen consumption per individual or per amount of mitochondria. So this helps us better understand how the mitochondria themselves are working. So a tissue can look impaired on the first measure purely because it may hold fewer mitochondria. even when every single mitochondrion inside the cell is performing normally. And in fact, when investigators looked at function per mitochondrion, the differences between the lean, the obese, and the diabetic muscles were no longer detectable. So the reduced capacity of the mitochondria in type 2 diabetes probably reflects just having fewer mitochondria rather than having mitochondria that aren't working so well.

18:46That's very, very important. So content and function per mitochondrion aren't the only dimensions, and they're not the same, though. And there's a third measurement here that neither of those can capture. Now, recall that mitochondria can continuously divide and fuse. The mitochondria are very dynamic. The balance between those two processes determines whether a cell maintains a connected network and high-functioning mitochondria or a scattered population of very small isolated fragments that don't work as well. That matters because the connected network can share the contents, it can distribute fuel more easily, and it can dilute the damage across a larger pool of mitochondria, while the fragments, they don't have that kind of buffer.

19:34In human muscle, the machinery for fusion appears suppressed in exactly the conditions we're discussing. Specifically, the expression of mitofusin 2, MFN2, that's a protein required for mitochondria to fuse together, is reduced in skeletal muscle from people with obesity and from people with type 2 diabetes, whether they are lean, leaner, or obese. And it also correlates negatively with body mass index and positively with insulin sensitivity. That fits the morphology described a moment ago where mitochondria in obese and diabetic muscle were about a third smaller than in lean muscle because they're just all perhaps split up.

20:19They've been forced apart. What pushes the balance of the mitochondria toward fission or division is at least partly influenced by the actions of a specific type of fat. Now, long-term students in the metabolic classroom have heard me discuss this particular fat before. It's called ceramides. Ceramides are a pretty obscure but very relevant type of fat that are known to accumulate in the muscle of obese, insulin-resistant people. In work from my lab, we found that ceramide exposure forces the mitochondria to very rapidly undergo fission. It pulls them apart. At the same time, it lowers the amount of oxygen the mitochondria are using while increasing the amount of hydrogen peroxide being produced.

21:06So more oxidative stress. All right, now up to this point, I think you have a better understanding of how mitochondria work and some of the things that can go wrong. If it's just a matter of the machinery being broken, well, then compounds, supplements, molecules that repair or bypass the machinery would be the logical fix. If the machinery works, but there is less of it, and it's more fragmented than it should be, and the amount of fuel arriving has gone up, then the problem is a mismatch between supply and capacity. That is a good opportunity to segue into the next point. All right, so this mismatch provides a product, a molecule, that we can see in a blood draw.

21:49When glycolysis generates pyruvate faster than the mitochondria can take it in and burn it, the excess pyruvate is converted to lactate. And that lactate can accumulate in the cell and then it gets exited from the cell and accumulates in the blood. Of course, when you think about lactate, you're thinking about exercise. You're associating this molecule with sprinting or high-intensity exercise. But that association is, I think, very narrow and even naive. It overlooks the fact that resting, fasting lactate carries a lot of information about mitochondrial capacity in someone who's not an athlete at all.

22:29In fact, it's one of the points that interests me so much about lactate and makes me personally excited about the upcoming use of continuous lactate monitors. I'm not as interested in the athlete as I am the person who looks at their lactate levels every morning and wonders what it may suggest about the mismatch between the fuel coming in and the mitochondria's ability to burn it. In a case cohort analysis within a large community-based study, fasting lactate rose in step with both fasting glucose and fasting insulin. And people in the highest lactate quartile had roughly twice the risk of developing diabetes compared with the lowest.

23:13In fact, so what we have here is that lactate had a predictive value beyond even when they controlled for things like body fat and these other usual risk factors, looking at lactate provided additional insight. And it's also something that moves, it improves with interventions that improve metabolic health. Now, there is a parallel signal on the fat side. So you'd say, well, lactate is the signal of the mitochondria not keeping up with glucose burning. What about the mitochondria not keeping up with fat burning? When fatty acids enter mitochondria faster than beta oxidation can break them apart or burn them, the partially processed intermediates accumulate and will exit the cell as a molecule called acylcarnitines.

24:02When you look at people with type 2 diabetes, you see this pattern consistent with the incomplete burning of these fats. So you end up getting less fat burning and more of these partially broken apart fats, where the mitochondria is trying to keep up with them, but it's being force-fed so many of these fatty molecules that it can't break them all the way down. So in other words, we're starting the pathway, but we can't finish them all off. and as we can as we look at this balance or this burning of glucose and fats it naturally brings us to insulin because insulin determines the mix of fuel that is coming into the cell and how well the cell can handle that fuel hyperinsulinemia can drive glucose into the cell while suppressing fat oxidation and insulin resistance at the fat cell means fatty acids are releasing into the bloodstream more than they should.

25:03So the insulin is no longer able to restrain or inhibit that breakdown of the fat from the fat cell. So you have the fat cell releasing more fat and you have tissues like muscle that are trying to keep up and burn them. So both of these substrates, glucose and fats arrive at the mitochondria simultaneously, but they're competing for the same limited pathway. No surprise when you think about this master metabolic hormone, And insulin dictates that both fuels show up at once when the cell can only fully process so much. So I hope you can understand the nuance that I'm presenting here. High insulin is pulling in more glucose into something like the muscle cell.

25:45But if the fat cells have become insulin resistant, they're also seeing a lot of free fatty acids from those fat cells. Normally, the muscle would burn those fat molecules very happily. But in the midst of high insulin, it can't because insulin inhibits beta oxidation. So you're not allowing the muscle to fully burn those fats. At the same time, you're forcing it to compete with glucose, not allowing the glucose to be fully burned, perhaps.

26:27fees or minimums. He'd also talk about how most Capital One cafes are open seven days a week to assist with your banking needs. Yep, even on weekends, it's pretty much all he talks about in a good way. What's in your wallet? Terms apply. See CapitalOne.com slash bank. Capital One N.A. Member FDIC. State Fair food is getting smaller and pricier. We'll have room for fried cookies. Okay, you never overspend on food. What's your deal? What's his deal? He went to Metro and got$450 in value on the new Samsung Galaxy A37 5G for free. And no activation fees. Free phone? Oh, sign me up. Get that more for your money feeling.

27:08Only on Metro by T-Mobile. Bring your number and activate$40 period plan. $450 based on device discount waived activation fee. Not available if with Metro or T-Mobile in the past 180 days.

27:20all right let's move on um so you're better understanding some of the the problems with mitochondrial function as it goes awry but what about measuring mitochondrial function to measure it properly it's harder it's harder than you might think the the clinical toolkit for measuring mitochondrial function was exclusively built to diagnose rare genetic congenital, in fact, inherited mitochondrial diseases. They're not designed to characterize mitochondrial capacity in just a person who's otherwise healthy, at least who does not have a genetic mitochondrial disorder, even if they're not so healthy because they have insulin resistance.

28:02Those clinical screenings don't work in these populations. So that brings me back to lactate. Fasting lactate is the simplest point, but it can be imprecise because of just being influenced by a lot of other variables like exercise or even a tourniquet on an arm being left on too long. Certain medications can increase lactate levels. Something that's impaired blood flow can increase lactate levels. That would kind of come back to the tourniquet. So lactate can be problematic as much as I like it. the lactate to pyruvate ratio was actually developed to help address and resolve some of this ambiguity and conflict because the balance between lactate and pyruvate depends on the ratio of loaded to unloaded nad in the cell the ratio reports on electron traffic rather than simply on fuel excess when the respiratory chain is blocked electrons back up nad stays loaded up and the ratio will climb, that lactate to pyruvate ratio.

29:05When the problem sits upstream at the entry into the mitochondria, lactate can be high while the ratio stays normal because pyruvate's also high. Altogether, it's elegant in principle, but it can become kind of difficult in practice because pyruvate is also very chemically unstable. So even if you are getting pyruvate measured at a clinic, you need to ensure that they're handling it very properly and adding the correct chemicals to prevent the pyruvate from being broken down too quickly. So it needs to be handled carefully and quickly. So many of the ratios that you may get from just routine practice are going to be heavily skewed to make it look like things are worse than they are, but it's maybe just a function of how they're handling the samples.

29:53The performance data also reflect some of this problem. In a study comparing biomarkers in children with confirmed mitochondrial disorders against children with other neuromuscular diseases and healthy controls, the lactate to pyruvate ratio was the weakest discriminator of everything tested. It's kind of discouraging. Now, what might be better? The better performers could be the mitokines, the stress signals that the cells will release when the mitochondria are compromised. A couple of them in particular, growth differentiation factor 15, GDF 15, and one you might have heard of before, fibroblast growth factor 21, FGF 21.

30:35They were both substantially elevated in children with mitochondrial disease. And in particular, GDF 15 gave the highest discrimination of any marker that was examined. The population these tests were built for is small. These are people with congenital mitochondrial problems. And the total prevalence of mitochondrial diseases in adults is fantastically low, like thankfully most congenital diseases are. But nevertheless, I think it helps point the direction with some things we could be focusing on. Lactate does matter. Lactate to pyruvate ratio does matter if you can get it. But then also these mitokines, if you can also get them, GDF-15 and FGF-21.

31:24Now, lest I sound too judgmental of them, I do want to defend them as much as I kind of presented a bit of a nuanced and even critical view. One other problem is that there are not enough data to give us validated tests. So if anything, you could look at your own numbers and then kind of monitor the trajectory. You comparing your numbers to someone else, it's going to make it a little more difficult and almost impossible if they're being handled by different labs. Okay, with these mechanisms and measurements in mind, let's shift the mini lecture to focus in the back half of this mini lecture on popular interventions that claim to help with mitochondrial fitness.

32:12One that's become popular is methylene blue. Methylene blue acts as an alternative electron carrier, accepting electrons and delivering them partway down that system, bypassing some of the earlier protein complexes that I mentioned. In a randomized double-blinded placebo-controlled study, the gold standard, 26 healthy adults were assigned to a single low oral dose or a placebo. So brain imaging observed increased activity in regions involved in attention and memory, along with a statistically significant 7 % increase in correct responses during memory retrieval tests. Now, that's a single dose, but if anything, you could say, well, that makes the results all the more impressive.

32:56They didn't look at any metabolic outcomes, unfortunately, but still, those were real changes. uroliothin a is another one and it is known to activate mitophagy you may hear in that word autophagy and that's on purpose that mitophagy is when the um the cell is cleaning out its mitochondria and it has the strongest human trial evidence of anything really in a four-month trial in adults that were older, 65 to 90. Urolythin A supplementation improved muscle endurance at the two-month assessment and shifted plasma biomarkers in a favorable way. But now it's not all sunshine and roses. The primary endpoints, like how long, how far could you walk in six minutes, it didn't differ from placebo.

33:47So it was not just all universally positive, but there was There was some evidence. In a separate four-month trial in middle-aged adults, muscle strength improved by roughly 12%, and plasma acylcarnitines, you'll remember those are the partially burned fats that sometimes reflect the mitochondria not keeping up, went down. So it does seem to generally improve the outcomes associated with improved mitochondrial function. with no fees or minimums on checking accounts. It's no wonder the Capital One bank guy is so passionate about banking with Capital One. If he were here, he wouldn't just tell you about no fees or minimums.

34:29He'd also talk about how most Capital One cafes are open seven days a week to assist with your banking needs. Yep, even on weekends, it's pretty much all he talks about in a good way. What's in your wallet? Terms apply. See CapitalOne.com slash bank. Capital One N.A. Member FDIC. State Fair food is getting smaller. And pricier. We'll have room for fried cookies. Okay, you never overspend on food. What's your deal? What's his deal? He went to Metro and got$450 in value on the new Samsung Galaxy A37 5G for free. And no activation fees. Free phone? Oh, sign me up. Get that more for your money feeling.

35:10Only on Metro by T-Mobile. Bring your number and activate$40 period plan. $450 based on device discount waived activation fee. Not available if with Metro or T-Mobile in the past 180 days.

35:22Coenzyme Q10. CoQ10 is another, it's an actual component of the electron transport system. It carries electrons from complex 1 to 3 as well as complex 2 to 3. An umbrella review of meta-analyses, so this is looking at a lot of studies, found that supplementation with CoQ10 was associated with reduced fasting glucose, which is, of course, a very meaningful marker. but some other markers, remember, this is kind of synthesizing or covering a lot of studies. Other things like fasting insulin and A1C, it still showed some significance, but they were much more modest changes. So that's where you would tease apart, well, it might have been statistically significant, but was it actually meaningful in the real world?

36:12Well, that's debatable. I'm sure the person who enjoyed any benefit at all would say it is worth it okay now let's go beyond what you put in your mouth and talk a little bit for a moment about what you just do to your body and there are two things there one of them is red and near infrared light this wavelength of light is actually absorbed by that final complex of the electron transport system that makes atp and it has been shown in humans that strong stimulation with these lights can measurably increase and activate that complex. So that's real evidence there. Also, cold exposure is important here.

36:56Cold exposure has been shown to significantly increase the expression of a molecule called PGC1-alpha. That is a master regulator of mitochondrial biogenesis. So the activating the production of new mitochondria. In human muscle biopsies, cold water immersion raised the expression of PGC-1-alpha by six times after three hours. Now, they weren't cold immersed for three hours, but three hours later, it was up by six times. And that even went beyond just exercise where they combined it with exercise or alone and it amplified the effect of exercise. That might be a reason to look at if you have the ability combining your workout or doing your workout after your cold immersion.

37:48Now, each of these either adds capacity or it adds a cofactor. It just improves electron flow, something like that. But that doesn't mean they're necessarily going to reduce the amount of fuel arriving at the mitochondrion. So the mitochondria may still be getting kind of overloaded with fuel. Now, all of these interventions and the earlier evidence, it suggests that the individual mitochondrion in insulin resistance and type 2 diabetes is not fundamentally broken. Even if the network that it's in is more fragmented than it should be, what has changed most is that the mitochondrial mass or the total amount of mitochondria has fallen while the delivery of substrate or fuel has risen.

38:35Now, again, rising lactate is the visible expression of glucose forced down the glycolytic route, but it can't get all the way into the mitochondria. And acylcarnitines going up is the kind of parallel version of that on the fat side. so adding something to improve the electron shuttling like methylene blue activating mitophagy with urelythin a or or stimulating the photons with red light or cold increasing pgc1 alpha all of that can help on kind of the consumption side but it's not necessarily going to be increasing although the cold could with pgc1 alpha the the capacity the the amount of mitochondria.

39:18So this brings us to the most powerful of all things, and it's going to be one that I'm afraid underwhelms you a little bit, and that is exercise. Exercise is the most reliable stimulus for increasing mitochondrial content in human skeletal muscle. In one study, in overweight older adults, they were assigned to either just weight loss through old-fashioned calorie restriction or exercise. Insulin sensitivity improved in both groups, but muscle biopsies showed that exercise increased mitochondrial content along with these electron transport proteins and fatty acid oxidation. The other just diet alone didn't.

39:57Now, substrate control or energy coming in control is the other variable here. Reducing the carbohydrate load lowers that glycolytic flux, that flow of glucose in very directly. That, of course, can reduce the pressure that forces the cell to undergo glycolysis and then resulting in just lactate accumulating. And lowering insulin by restricting dietary carbohydrates can restore the cell's ability to burn fat rather than holding on to both fuels, kind of locking them up in the queue at the same time. Now, there's a second consequence, of course, to lowering the carbohydrate load that's easy to overlook.

40:38And that is that when carbohydrate is restricted and insulin lowers enough, the liver produces ketones. And beta-hydroxybutyrate, BHB, turns out to be more than a fuel. It acts as a signal that changes how mitochondria behave. And what it does depends on the tissue. And this is work directly from my lab. In fat tissue, we found that beta-hydroxybutyrate will raise mitochondrial respiration. So they're consuming more mitochondria, but it's not making more ATP. So it's uncoupling the mitochondria in fat tissue, including we found this happening in fat tissue from humans, where we found that when we measured a fat biopsy from humans in ketosis, it showed a respiration rate or how much oxygen it was consuming went up by about 130 % or so.

41:32So a significant, more than twofold, almost two and a half times compared to the people who were not in ketosis. Now in skeletal muscle, the effect actually kind of runs the other way. We found that rather than uncoupling, BHB tightened the link between respiration and ATP production. And it actually resulted in less hydrogen peroxide being produced. So the same molecule loosens coupling in fat and tightens it in muscle. So dissipating energy where energy is stored and improving efficiency where energy is used. In closing, mitochondrial capacity can become limiting in insulin resistance and type 2 diabetes.

42:16And lactate is probably, it's among the earliest accessible, in other words, easily measured signals that the limit is being reached. There are certainly some interventions that can help improve mitochondrial function. I've mentioned them. Exercise is best, just old-fashioned, boring exercise, and it increases the number of mitochondria you have, and it helps control the fuel load so that it helps prevent the mitochondria from being overwhelmed. Everything else I think should be viewed as an addition to this intervention. It's definitely not a substitution for it. Class dismissed. Until next time, more knowledge, better health.

43:26We'll see you next time. Yep, even on weekends, it's pretty much all he talks about, in a good way. What's in your wallet? Terms apply. See CapitalOne.com slash bank. Capital One N.A. Member FDIC. State Fair food is getting smaller. And pricier. We'll have room for fried cookies. Okay, you never overspend on food. What's your deal? What's his deal? He went to Metro and got$450 in value on the new Samsung Galaxy A37 5G for free. and no activation fees. Free phone? Oh, sign me up. Get that more for your money feeling only on Metro by T-Mobile. Bring your number and activate$40 period plan. $450 based on device discount wage activation fee.

44:08Not available if with Metro or T-Mobile in the past 180 days.