What this covers
Do you feel like you're running on a half-charged battery no matter what supplements you take? The problem might not be your supplements — it might be your mitochondria. In this video, Dr. Ashley Froese breaks down exactly how your mitochondria work, where energy production actually breaks down, and which interventions (CoQ10, NAD, urolithin A, cold exposure, fasting, and more) target which specific parts of the machine.
My preferred NMN for NAD+: https://bit.ly/4ta7SAd (This is an affiliate link which means I made a small commission off sales at no extra charge to you.)
This video is for educational purposes only. Dr. Froese is a board-certified physician, but this content does not constitute medical advice and is not a substitute for a conversation with your own healthcare provider. Always consult your doctor before starting any supplement or health intervention.
Timestamps: 0:00 — Introduction: Are your supplements working? 0:55 — What is a mitochondria? (Structure explained) 4:47 — The electron transport chain (how ATP is made) 6:40 — CoQ10: how it works & why statins deplete it 8:13 — NAD supplementation (NMN/NR explained) 9:59 — Mitophagy: recycling broken mitochondria 11:00 — Mitochondrial biogenesis & PGC1alpha 11:35 — Urolithin A: what it actually does 12:23 — Supplement summary: which targets which problem
Source description (no synthesized summary yet).
Mitochondrial dysfunction results from membrane degradation, enzyme damage, and failed cellular recycling processes, and effective interventions must target the specific broken component rather than applying generic supplements.
- Mitochondrial problems stem from multiple distinct failure points (membrane structure, cristae folding, electron transport chain, matrix function, ROS damage) not just energy production capacity
- Most supplements work by supporting specific stages of the energy production assembly line, not by magically creating energy from nothing
- Exercise is uniquely effective because it activates mitophagy and biogenesis, the cellular mechanisms that remove broken mitochondria and build new ones
This asset isn't compiled yet
You're seeing its claims, ranked. Compile it to build the argument threads, weight them, and check each claim against your library — the full view.
Mitochondrial biogenesis is the process of building new mitochondria controlled by a master switch called PGC1 alpha; when PGC1 alpha is activated, cells receive the signal to build more mitochondrial power plants, and interventions including exercise, fasting, cold exposure, elevated NAD levels, and certain peptides can activate mitochondrial biogenesis.
“Now, if mitophagy is the demolition crew, your body also needs ways to make new mitochondria. And that's called mitochondrial biogenesis. Biogenesis literally just means creating new life, or in this case, building new mitochondria. The master switch controlling a lot of this process is called PGC1 alpha. And when PGC1 alpha gets activated, your cells get the message, 'Hey, we need more power plants. We need more mitochondria.' So, if you think about all the biohacks that we're interested in, exercise, fasting, cold exposure, even higher NAD levels, and certain peptides, well, these can all help activate mitochondrial biogenesis.”
Excessive reactive oxygen species from stress, illness, inflammation, poor diet, and bad sleep damage multiple mitochondrial components (DNA, cristae, electron transport chain enzymes) and create a vicious aging cycle where damage increases ROS production, which increases damage further.
“But, if the sparks are constantly flying everywhere from excessive stress, illness, inflammation, poor diet, bad sleep, you get the picture. Well, everything starts catching fire. And over time, excessive reactive oxygen species can damage the mitochondrial DNA. It can damage the cristae, and even damage parts of the engine itself.”
About 1 to 2% of oxygen that moves through the electron transport chain leaks out and creates reactive oxygen species (ROS), which function as tiny sparks flying off machinery; small amounts of ROS are normal and the body uses them for signaling and adaptation, but excessive ROS from stress, illness, inflammation, poor diet, and bad sleep can damage mitochondrial DNA, cristae, and engine components, perpetuating a vicious aging cycle.
“Remember the engines we just talked about? Well, they're incredibly efficient, but they're not perfect. About 1 to 2% of the oxygen that gets moved through that system leaks out and creates something called reactive oxygen species or ROS. And you can think of reactive oxygen species like tiny little sparks flying off of the machinery. A few sparks is totally normal and fine. In fact, your body actually uses small amounts of these sparks for signaling and adaptation. But, if the sparks are constantly flying everywhere from excessive stress, illness, inflammation, poor diet, bad sleep, you get the picture. Well, everything starts catching fire. And over time, excessive reactive oxygen species can damage the mitochondrial DNA. It can damage the cristae, and even damage parts of the engine itself. And this is one of the reasons that aging is a very vicious cycle. More damage creates more dysfunction, more dysfunction creates more reactive oxygen species, and the cycle keeps feeding itself.”
Exercise is one of the strongest known signals for improving mitochondrial structure over time and is uniquely effective compared to supplements at maintaining or restoring inner membrane cristae folding.
“Now, you may want to know which supplements fix this, and I'll give those to you. But hear me out because this is one of the very few places where exercise absolutely dominates supplements. According to research, consistent exercise is one of the strongest signals we know of for improving mitochondrial structure over time.”
Mitophagy is the cellular process of recycling damaged mitochondria through identification, tagging, breakdown, and reuse of useful pieces—essentially controlled demolition—which slows down with age, sedentary behavior, and metabolic dysfunction, allowing broken mitochondria to persist and create inflammatory byproducts and additional dysfunction.
“Your mitochondria aren't permanent workhorses. You're actually supposed to kill off broken ones and build new ones constantly. The process of recycling mitochondria is called mitophagy. Literally translated, it means eating mitochondria. So, your cells identify damaged mitochondria, tag them for removal, break them apart, and recycle the useful pieces. It's basically controlled demolition. The sad thing is that as we age, become more sedentary, and develop metabolic dysfunction, well, that cleanup process starts slowing down. And suddenly, the broken mitochondria stick around and create a whole bunch of inflammatory byproducts. And instead of a factory full of efficient workers, now you've got a bunch of malfunctioning equipment hanging around just collecting paychecks. Interestingly, those dysfunctional mitochondria can create even more dysfunctional mitochondria. So, the problem really starts compounding over time.”
Urolithin A is a compound produced by gut bacteria when eating foods like pomegranates; research shows it helps the body identify and remove damaged mitochondria that shouldn't persist, making it a targeted intervention specifically for mitophagy rather than energy production.
“So, urolithin A is a compound that you actually make through your gut bacteria when you eat foods like pomegranates. And what's cool here is that researchers have been studying it because of its effects on mitophagy. And the research suggests that it helps your body identify and remove the mitochondria that shouldn't still be there. And see, if you're just trying to supplement for mitochondrial health and you don't actually know what you're targeting, it can kind of get messy. So, know that if you're using urolithin A, this is what you're doing. You don't always have to focus on boosting the engine. Sometimes you do need to focus on mitophagy and then boosting the energy.”
Chronic inflammation, aging, insulin resistance, and poor metabolic health can change the structure of the mitochondrial outer membrane and stiffen it, preventing nutrients and signals from moving in and out properly—a phenomenon called signal interference that may cause fatigue before energy production capacity is even compromised.
“Chronic inflammation, aging, insulin resistance, which happens when you're overweight or have diabetes, and poor metabolic health in general can change the structure of this outer membrane and stiffen it. And now things can't move in and out the way that they're supposed to. Very important signals now have a harder time getting their messages across. Sometimes fatigue doesn't start because your mitochondria can't make energy. Sometimes it starts because of this. I call it signal interference.”
The body uses small amounts of reactive oxygen species for normal cellular signaling and adaptation, meaning ROS is not universally harmful but becomes pathological only when produced excessively.
“A few sparks is totally normal and fine. In fact, your body actually uses small amounts of these sparks for signaling and adaptation.”
CoQ10 works by helping shuttle electrons through the electron transport chain assembly line, effectively keeping traffic moving through the power plant; statins block the body's natural CoQ10 production, which is why supplementation is recommended for people taking statins.
“CoQ10's job is to help shuttle electrons through this assembly line. It's basically helping traffic move through the power plant. Statins, our famous cholesterol medications, can block your body's natural production of CoQ10. And that's why we recommend supplementing with it if you take statins.”
The lipid composition of the mitochondrial outer membrane can be improved by eating antioxidants (berries and colorful foods), omega-3 fatty acids (fish like sardines or high EPA/DHA supplements), and phosphatidylcholine, which is the primary structural ingredient of the mitochondrial membrane itself.
“The way you do this is by changing the lipid composition of this wall and stopping the structural degradation that's caused by inflammation or burning the candle at both ends. You can think of the outer membrane like a fluid security fence. If it gets packed with the wrong fats or becomes too rigid from inflammation, the gates rust up. And so my favorite thing to tell people here is to eat more antioxidants. Just think berries and colorful foods here. Also, omega-3 fatty acids, fish like sardines or supplements with high EPA and DHA. This is a big reason why these are important. Phosphatidylcholine, this is a supplement that you can take, but it's the primary ingredient that makes up the structure of this mitochondrial membrane.”
Dysfunctional mitochondria persist in aging organisms because the mitophagy cleanup process slows down with age, sedentary behavior, and metabolic dysfunction, creating a situation where 'malfunctioning equipment hangs around just collecting paychecks' instead of being removed.
“The sad thing is that as we age, become more sedentary, and develop metabolic dysfunction, well, that cleanup process starts slowing down. And suddenly, the broken mitochondria stick around and create a whole bunch of inflammatory byproducts. And instead of a factory full of efficient workers, now you've got a bunch of malfunctioning equipment hanging around just collecting paychecks.”
Omega-3 fatty acids (from fish like sardines or high EPA/DHA supplements) are important for mitochondrial health because they help maintain proper lipid composition of the outer mitochondrial membrane, preventing stiffening and allowing nutrient/signal flow.
“Also, omega-3 fatty acids, fish like sardines or supplements with high EPA and DHA. This is a big reason why these are important.”
The inner mitochondrial membrane can be compared to an accordion whose folds (cristae) are deliberately designed to create massive surface area for housing energy-producing enzymes; flattening of this accordion structure with age and stress reduces the available surface area for ATP production.
“These wrinkles or folds are called cristae. They're like an accordion. And the reason for this is that your body takes a pretty small membrane and folds it over and over and over again to creating massive amount of surface area.”
The electron transport chain can be understood as a factory assembly line with five stations (complexes), where electrons move through the line while protons pump across the membrane, and this process is analogous to pumping water uphill into a reservoir, storing potential energy that drives ATP synthesis.
“Now, you have a separation of charge and concentration, which creates stored potential energy. You can think of it like pumping water uphill into a reservoir. Lots of potential energy being made here.”
Complex 5 of the electron transport chain functions like a turbine that spins as protons rush back through it, generating ATP energy; this turbine metaphor shows how stored potential energy (the proton gradient) is converted into mechanical work that powers ATP synthesis.
“And eventually, they rush back through complex five, which is like a turbine that spins and creates ATP energy as long as the electrons make it down the line.”
The inner mitochondrial membrane contains cristae, which are deeply folded structures that increase surface area to house more ATP-producing enzymes; healthy metabolically active mitochondria have tightly organized inner membranes with very deep folds, while older stressed and damaged mitochondria have flattened folds that produce less ATP.
“This inner membrane isn't smooth like the outer one. It's very wrinkled up. And if you learn anything, know that this is completely intentional. These wrinkles or folds are called cristae. They're like an accordion. And the reason for this is that your body takes a pretty small membrane and folds it over and over and over again to creating massive amount of surface area. Because this is where the engines for your energy live. And more folds means more room for engines. More engines means more ATP, and more ATP means more energy.”
Complex 1 of the electron transport chain is where most damage occurs from age and inflammation, making it a primary failure point in aged and dysfunctional mitochondria.
“Unfortunately, complex one is where most damage occurs from age and inflammation, just like the outer membrane.”
NAD supplementation (such as NMN) supports the Krebs cycle by increasing available NAD, which eventually becomes NADH—one of the main energy delivery trucks feeding the electron transport chain—rather than creating energy from nowhere.
“Anyway, it's here that supplementation with NAD can be useful. So, a lot of people think taking supplements for NAD creates energy out of nowhere, but it's really just support for the assembly line. NAD eventually becomes NADH, one of the main energy delivery trucks feeding the electron transport chain.”
Antioxidants from berries and colorful foods help restore mitochondrial outer membrane function by reducing inflammation-induced structural degradation and preventing the membrane from becoming too rigid.
“And so my favorite thing to tell people here is to eat more antioxidants. Just think berries and colorful foods here.”
The electron transport chain is a five-station assembly line (complexes 1-5) living on the folded inner mitochondrial membrane where NADH and FADH2 (energy delivery trucks made from broken-down food) drop off electrons; the electrons move through the chain while protons are pumped across the membrane, creating potential energy, and eventually protons rush back through complex 5 (a turbine) to generate ATP.
“This is the electron transport chain. Now, the electron transport chain isn't a magical merry-go-round. It's really a five-station assembly line that lives on that folded-up inner mitochondrial membrane. If you've ever wondered how or why CoQ10 supplements work, this is the stuff that you need to know. Think again about a factory assembly line here. You have station 1 2 3 4 and 5, formally called complexes 1 2 3 4 and 5. And from start to finish, when you eat food, you end up breaking it down into NADH and FADH2. Think of these as like energy delivery trucks. And something important here is that the H in both of these are hydrogen atoms, which consist of one proton and one electron. When NADH arrives at complex one, it drops off electrons. The electrons continue moving through the chain, the assembly line. The protons get separated and pumped across the inner mitochondrial membrane. Now, you have a separation of charge and concentration, which creates stored potential energy. You can think of it like pumping water uphill into a reservoir. Lots of potential energy being made here. You get a ton of potential energy building up with the protons moving through the membrane. And eventually, they rush back through complex five, which is like a turbine that spins and creates ATP energy as long as the electrons make it down the line.”
The mitochondrial matrix (the 'soup' in the center of the mitochondria) is where food gets processed by the Krebs cycle (also called the citric acid cycle or TCA cycle) into NADH and FADH2, the energy delivery trucks that feed the electron transport chain.
“In fact, where a lot of damage actually starts is in the center of the mitochondria, past the inner mitochondrial membrane. This is where the mitochondrial matrix is, which is like the soup in the middle. This is where your food actually gets processed. So, remember the energy delivery trucks we just talked about, NADH and FADH2? Well, this is where most of them get loaded up with their cargo. The matrix contains the Krebs cycle or the citric acid or TCA cycle. This is where all of that happens. This is where your food gets broken down into the NADH and the FADH2. You eat food, the Krebs cycle breaks it apart, and then in return it loads up those little delivery trucks with cargo that can be delivered to the engines.”
Mitochondria have their own DNA located inside them (separate from the cell nucleus DNA); this mitochondrial DNA is where damage accumulates from reactive oxygen species and other sources, creating a vicious cycle where damage leads to more ROS production and more DNA damage.
“Now, for a fun fact, most of our DNA lives in our cells' nucleus, but the mitochondria, despite living outside of the cell nucleus, actually has its own DNA. Unfortunately, this is also where damage starts accumulating.”
Phosphatidylcholine is the primary structural ingredient that makes up the mitochondrial membrane, making supplementation with it directly support membrane structure and function.
“Phosphatidylcholine, this is a supplement that you can take, but it's the primary ingredient that makes up the structure of this mitochondrial membrane.”
The goal of electron transport chain supplements like CoQ10 and methylene blue is not to create ATP directly, but rather to keep the assembly line moving efficiently by maintaining electron flow.
“The goal here isn't to create ATP directly. The goal is to keep the assembly line moving efficiently.”
Riboflavin is a supplement that can help support the electron transport chain when it is slowing down, functioning alongside CoQ10 as an intervention for engine problems.
“If the engine is slowing down, well, that's where CoQ10, riboflavin, and potentially methylene blue fit.”
The effectiveness of mitochondrial supplements depends on which component of the mitochondrial system is actually broken; membrane problems require omega-3s, phosphatidylcholine, and metabolic health improvements; flattened cristae require exercise as the primary intervention; slow electron transport requires CoQ10, riboflavin, and possibly methylene blue; matrix/NAD insufficiency requires NMN or similar NAD precursors; and quality control problems require urolithin A, fasting, cold exposure, and exercise.
“And now I hope you can see why there isn't one best mitochondrial supplement. There's just different interventions that target different parts of the machine. If the membrane's the problem, think omega-3s, phosphatidylcholine, and improving metabolic health. If the inner mitochondrial membrane is flattening out, exercise is a very big deal here. There are also peptides that can kind of stabilize that, but that's another subject for another day. If the engine is slowing down, well, that's where CoQ10, riboflavin, and potentially methylene blue fit. But please talk to your doctor about that one. And if they don't know, at least watch my videos around that. If the matrix needs support or you just need more NAD, well, that's where supplements like NMN like this one enter the conversation. And if you want the link for this one in specific because it's my favorite, you can get the link for that in the description. If quality control is a problem, that's where urolithin A, fasting, cold exposure, and also exercise can help remove mitochondria and build new ones.”
Methylene blue helps pick up electrons that get stuck in damaged electron transport chain complexes and continues moving them along the assembly line, making it a useful intervention for restoring electron flow when complexes are impaired.
“The popular supplement methylene blue, which arguably a lot of people don't understand how it works, well, it can actually help pick up electrons that can get stuck in damaged complexes and continue moving them along the assembly line, which is really cool science.”
Fatigue often originates from structural problems like outer mitochondrial membrane stiffening that prevent nutrient and signal flow, not from energy production capacity being exhausted.
“Sometimes fatigue doesn't start because your mitochondria can't make energy. Sometimes it starts because of this. I call it signal interference.”
Damaged mitochondria can create more dysfunctional mitochondria, meaning mitochondrial dysfunction compounds over time as broken mitochondria clone their dysfunction to neighboring mitochondria if mitophagy is not working properly.
“Interestingly, those dysfunctional mitochondria can create even more dysfunctional mitochondria. So, the problem really starts compounding over time.”
Instead of randomly throwing interventions at mitochondrial health, one should know exactly which part of the mitochondrial machine is broken before selecting an intervention, because different problems require fundamentally different solutions.
“I'm hoping that by now, instead of throwing random interventions at your mitochondria, you know exactly which part of the machine you're trying to fix when you hear all about these mitochondrial supplements and peptides.”
Understanding mitochondrial anatomy and how different interventions work on specific components is important because it allows people to avoid wasting time and money on supplements that don't address their actual problem.
“And hopefully now you understand why this is all so important.”
The outer mitochondrial membrane can be thought of as a 'fluid security fence' that maintains its function through proper lipid composition; when packed with the wrong fats or made rigid by inflammation, the gates rust up and prevent molecular passage.
“You can think of the outer membrane like a fluid security fence. If it gets packed with the wrong fats or becomes too rigid from inflammation, the gates rust up.”