What damages mitochondria?
Dr. Chris Palmer is an Associate Professor of psychiatry at Harvard and author of the new book Brain Energy, which argues that the association between mental disorders and metabolic dysfunction is so strong that what is currently conceptualized as psychiatric illness should instead be considered a problem of mitochondria.
Given the importance of mitochondrial function in maintenance of mental health and general well-being, it behooves us to understand better the causes of mitochondrial injury (and their resulting metabolic disorders) in the first place. I recently finished a new book called Mitochondrial Intoxication (de Oliveria 2023) that contains about 700 pages of deep research into the many harms that can befall the mitochondria, but the fact is that the book isn’t very helpful for what I’m trying to do. It focuses on exposures to chemical agents — i.e., poisons — that damage mitochondria. For example, there’s an interesting contribution on aluminum, which is the third most abundant element in the earth’s crust. You wouldn’t think that aluminum would be a problem for human beings, because we have so much evolutionary exposure to aluminum in soils. However, the chemical form of mineral aluminum means that it’s bound up in silicates (i.e., clay, silt — what most people would call dirt) and is generally not bioavailable. Only in industrialized, adulterated forms is aluminum liberated from its mineral form to become absorbed through the gastrointestinal tract into the bloodstream. Once there, it can cause havoc.
Nonetheless, what’s more interesting to me is the everyday, chronic stressors that damage mitochondrial processes and result in the metabolic disorders that are now routine among Americans and others living in industrialized countries. There is precious little investigation of the mechanisms by which or diet and non-chemical exposures impact mitochondria, and an urgent need for new hypotheses.
To that end, I speculate that there are principally three pathways to mitochondrial injury:
1. excess carbohydrate intake,
2. excess seed oil (e.g., corn, soybean, cottonseed, and all other so-called vegetable oils) intake, and
3. disruption of circadian rhythm.
In the paragraphs below, I’ll describe these hypotheses in further detail and the mechanisms that support them. Then, I’ll tell you several things you can do to support your mitochondrial health, and thus protect yourself from the mental and other disorders that can result from mitochondrial dysfunction.
Excess carbohydrate intake
All digestible carbohydrates are eventually converted into glucose in the bloodstream. Simpler carbohydrates reach the bloodstream faster. For example, the sugar in fruit juice and soda can enter the body through the blood vessels in the mouth. Concentrated liquid carbs will raise blood glucose without even reaching the stomach
Once in the bloodstream, glucose must either be used immediately for the energy to power exercise, growth, wound repair, thinking, or other bodily functions… or it must be stored. The body has very few reservoirs for glucose storage. The most significant is in the liver, in a form called glycogen. From an energetic perspective, liver glycogen stores are not a long-term or lasting reservoir of energy. They exist to provide a quick boost of in times of crisis.
The vast majority of energy reserves in the body are stored in white fat cells, which means excess glucose in the bloodstream that is not used for exercise or other purposes in the body must be converted into fats first. That conversion also happens principally in the liver.
One of the peculiar characteristics of the human body is that transport of glucose from the bloodstream into liver and other cells is surprisingly slow without the aid of insulin. That is, for reasons that are not obvious but that I will speculate about here, glucose (mostly) requires the aid of insulin to cross the cell membrane.
In bodies that do not suffer from Type 1 diabetes, insulin is produced by the islet cells in the pancreas.[1] The higher blood glucose levels rise, the more insulin is produced to help shuttle that glucose across the membranes that define liver, muscle, brain, brown & white fat cells, and other cells in the body, where it can be processed by mitochondria.
The problem is that excess carbohydrates flood the bloodstream with glucose, which overload the mitochondria, causing the over-production of what are called reactive oxygen species (ROS). Mitochondria are responsible for producing the energy carriers that fuel almost every energetic process in the body, including repair of other cells and their components. However, in the course of their chemical energy conversion functions, mitochondria inevitably miss a few electrons. Like sparks coming off the motor of a toy electric train, these electrons wind up in the wrong place, leaving vacancies in the molecules that were supposed to receive them. Those molecules, like hydroxyl radical or superoxide, are powerful oxidizing agents that typically attack whatever hydrocarbon might be in close proximity -- in a search for their missing electrons.
All too often, the molecules in close proximity that wind up getting destroyed are the mitochondrial DNA (mDNA) that govern the conversion of glucose in the first place. Fortunately, mitochondria are equipped with several defense mechanisms to protect the integrity of their mDNA. The first of these is melatonin, which I’ll describe in more detail later. For now, it’s sufficient to mention that mitochondria produce their own melatonin to scavenge ROS and prevent mDNA damage. Also, ROS will signal two processes called mitophagy and mitobiogenesis. The first destroys damaged mitochondria, while the second produces new mitochondria by replicating those the body senses are not damaged.
So some ROS production is healthy, so long as the mitochondria have sufficient melatonin to donate electrons and the mitochondria have enough time to recovery from glucose overload by undergoing mitophagy and mitobiogenesis. However, too much carbohydrate, for too long, without periods of fasting or ketosis to allow for mitophagy and mitobiogenesis can cause chronic dysfunctions in mitochondria.
Type 2 diabetes is a condition in which the islet cells of the body produce plenty of insulin, but the cells become resistant to its action. As a consequence, glucose ingested in food builds up in the bloodstream, instead of flooding the mitochondria. To date, I have yet to read a cogent explanation of the evolutionary advantage that insulin resistance might confer to the ancient human beings. Given the deleterious long-term health consequences of insulin resistance, the failure to explain its evolutionary function presents quite a conundrum. In fact, every leading cause of death from chronic illness, including cancer, is associated with insulin resistance.
So why should insulin resistance exist at all, if it leads to the long, slow premature death of those who suffer from it?
In science, some of the most insightful hypotheses are put forth to resolve the conundrums and paradoxes that defy explanation under current thought paradigms. It is in that spirit that I will offer the following idea.
It may be that Type 2 diabetes is an evolutionary adaptation for protecting mitochondria from glucose overload. When carbohydrate intake is too high and blood glucose spikes, cells that becoming resistant to insulin will protect their mitochondria from further damage. By keeping the glucose in the bloodstream for later processing (e.g., into synthesis of fat), insulin-resistant cells protect their precious mitochondria from being inundated with glucose that could cause overproduction of mitochondria-damaging ROS. If the consequences of excess insulin and elevated blood sugars are bad (and they are), but the consequences of mitochondrial damage are worse – or at least more immediate – than insulin resistance is a rational evolutionary adaptation that would preserve the human body for long enough to reproduce and nurture offspring.
Excess seed oils
Fats are much more complex molecules than carbohydrates. While it is true that the basic chemical formula for carbohydrate can come packaged in several different sizes and configurations, their structure, action, and conversion is simplistic compared to fats – which is why it seems that there are many different ways of classifying, categorizing, or naming different fat molecules than there are ways to distinguish among the carbohydrates. For example, in this book I will sometimes use the terms oil, fat, fatty acid, lipid, and triglyceride as if they were all interchangeable – even though they are different in their chemical structures and properties.[2]
For our purposes, we will make broad distinctions between three different sources of dietary fats, rather than delve deep into their compositions. These sources are 1) seeds, 2) fruits, and 3) animals.
Seed oils are extracted from grains like corn, flax, sunflower, and safflower, from beans like soybean and peanuts, or from nuts like walnuts. Seed oils can even be extracted from inedible crops like cotton and rapeseed (canola) and added to foods as long as they are chemically detoxified prior to human consumption. Seed oils can also be extracted from the pits (or stone) inside a fruit, like grapeseed oil.
The problem with seed oils, from the perspective of the plant, is that it serves no evolutionary, reproductive purpose to encourage most animals to eat their seeds. For example, eating corn kernels largely destroys their germination viability. In some cases, seeds can survive through the digestive tract of birds or rodents and be passed back to the soil in guano or feces -- so ingestion in some cases is not always fatal. Nonetheless, cottonseed and rapeseed toxicity is an evolutionary biological defense mechanism intended to maintain the reproductive viability of the plant. That is, seeds are well-defended against giving up their nutrients, which may explain the human technologies of shelling, grinding, fermenting, and baking that make seeds more digestible.
On the other hand, fruit oils are generally more accessible, healthier, and nutritious. For example, olive oil is extracted from the fruity mesocarp of the olive – the part that surrounds the seed, rather than the seed itself. The same is true of avocados. From an evolutionary perspective, the fruity part is a reward that would attract animals and encourage consumption. The seed inside the fruit is still well defended, so that it will pass through the digestive tract of the animal and be deposited in nitrogen-rich feces at some distance from the parent plant, where hopefully the seed will germinate into a new, flowering plant. Fruits are designed by evolutionary selection to be nutritious, while seeds (and pits, stones, or nuts) are designed to discourage consumption.
Finally, there are animal fats, which cannot be harvested from passive plants. Animals defend their flesh with fangs & claws, venom, and sharp teeth. Unlike stationary plants, animals can also run from predators. Their fats are not designed for chemical defense. Rather, animal fat has evolved to serve as rich energy source to fuel other defense mechanisms – like fight and flight.
Thus, it is no evolutionary accident that the chemical composition of seed oils is not favorable for human consumption. Fruit oils are more favorable, and animal fats are generally the best. The analysis of these oils characterizes them into omega-3, omega-6, and other complex classifications that make more subtle distinctions regarding their nutritional content, but these aren’t necessary for our purposes.
You might say, “What does the chemical composition of dietary fat even matter for? When fat is oxidized for energy, all different forms are broken down into carbon dioxide and water, and expunged from the body after the energy is extracted!”
That’s true.
Except that dietary oils are not used solely for energy. They are also used as building materials within the body. For example, cell membranes are made up of phosolipids – combinations of fatty acids that are hydrophilic on one end and hydrophobic on the other. That is, the types of oils in your diet provide the building blocks for your body, including your cell membranes.
When there are too many seed oils in your diet, compared to fruit oils and animal fats, the body has no choice but to incorporate the seed oils into the material structure of your body. I’ll refer back to this again in the chapter on evolution of the human brain, because it relies on a high concentration of fats that can only be obtained from aquatic sources – such as shellfish. However, in this description of insulin resistance our focus is not so much on the brain, but on the cell membrane.
Suppose, for example, that the body preferentially partitions the omega-3 fatty acids in the diet for brain development. What would that leave for construction of cell membranes when seed oils are disproportionately high in the diet? The omega-6 fatty acids in seed oils will be all the body has left, and it will construct cell membranes from those.
Here's where I’m going to offer you some more speculation. The structure of seed oils is different from fruit and animal oils. It stands to reason that the phospholipids from which your cell membranes are constructed have a different structure when they’re built from seed oils, than when their built from animal fat. It may be that differences in the chemical structure of these phospholipids is what causes them to be less efficient for the passage of glucose, regardless of insulin.
In other words, a body with low carbohydrate intake but high in seed oils will not modify the action of the cell membrane for insulin resistance as an adaptation to protect mitochondria from glucose overload. Rather, it will develop insulin resistance because the phospholipids in the cell membrane are dysfunctional — because they have been constructed from the wrong type of fatty building blocks.
While insulin resistance from carbohydrate overload can be remedied in less than two weeks, because the processes of mitophagy and mitobiogenesis are comparatively fast, insulin resistance from excess seed oils consumption will be more persistent. Rebalancing oils in you diet can happen fast, but rebalancing them in the structure of you body takes years, as molecular turnover in cell membranes is comparatively slow.
Circadian rhythms
It came as a revelation to me that mitochondria make their own melatonin. My understanding had always been that melatonin is synthesized in the pineal gland, deep inside the brain, in response to darkness to help regulate sleep and the circadian clock.
I wasn’t wrong, but I wasn’t entirely right, either,
It was Dr Joe Mercola who corrected me. He lives in Florida now, and enjoys biking down to the beach for a walk. It was during one of those beach walks that we were talking on the phone, and he expressed absolutely zero interest in cold water immersion. Since that’s my thing, it wasn’t clear that our conversation was going anywhere… . He probably felt the same way, because he offered to change the subject.
“You know, Tom, mitochondria make their own melatonin,” he told me.
The fact is that I did not know. It was the fist time I’d ever heard of such a thing.
So Dr. Mercola took the time to explain it to me, and to send me a journal article on the topic.
Once you understand that melatonin is essential for protecting mDNA against ROS damage, then you have to realize that the melatonin synthesized in the pineal glad can’t possibly reach the mitochondria in the liver in a time frame that is fast enough to respond to ROS overload. It’s too far from the pineal gland in the brain to mitochondria everywhere else in the body. Carbohydrates will get there much faster than melatonin from the pineal gland, and then where would the mitochondria be if they had to rely on the pineal gland for their principal chemical defense?
So mitochondria make their own melatonin.
According to a theory first proposed by Lynn Margulis in 1967[3], mitochondria originated as independent prokaryotic organisms in the primordial soup from which all life emerged more than three billion years ago.[4] It wasn’t until they were subsumed by more complex eukaryotic organisms that they were relegated to the subservient role of organelle, rather than independent organism.[5] Nonetheless, mitochondria were once entirely viable organisms in their own right, and it was at this time that they developed the essential capacity to synthesize their own melatonin.
Melatonin is an ancient antioxidant (Reiter et al. 2017). That is, its function as an antioxidant precedes its function in circadian regulation by several billion years on the evolutionary timeline. The two functions are likely related, as the necessity of antioxidants varies in accordance with exposure to sunlight. Nonetheless, the essential point is that melatonin is both produced in the mitochondria and essential to protection of mDNA.
When your sleep and circadian rhythm is disrupted by overexposure to artificial light and underexposure to sunlight – i.e., by malillumination – melatonin production in your mitochondria may suffer, leaving them vulnerable to damage. And what happens when mitochondria are damaged?
Insulin resistance.
Practices that protect mitochondria
There are several things you can do to avoid mitochondrial injury:
Minimize seed oils in your diet. Eat fish, shellfish, animal fats, and occassionaly fruit oils like olive, coconut, and avocado oil instead. The more wild the animal, generally the better the fat profile. For example, wild fish is better than farm-raised. And pasture-raised beef, pork, chicken, and duck are better than animals that are raised in Confined Animal Feeding Operations (CAFOs).
Maintain good light hygiene. Another way to say this is to avoid malillumination. That means minimizing exposure to artificial lights — especially fluorescent or white LED lights at night. During the day, high efficiency windows prevent exposure to both the ultraviolet and infrared parts of the sunlight spectrum, impoverishing your body of the invisible wavelengths that it is evolutionarily evolved to expect. To make matters worse, most modern buildings rely on artificial, high-efficiency fluorescent or LED lights for illumination during the day. This fact is ironic when you consider the ubiquitios modern high-rise building is typically clad in glass. Nevertheless, the daytime lighting inside is more often provided from fluorescent tubes than from the sun, further contributing to day-time malillumination. At night, exposure to the blue light from computer and smartphone screens postpones melatonin production, delays the circadian clock, and further compounds the malillumination that built up during the day.
To fix the broken patterns of light exposure, it’s helpful to wake up before dawn. Get some of the early daytime light — e.g., civil twilight — into your eyes by going outside without your eyeglasses on. Don’t wear contact lenses or any type of glasses. Just bathe yourself in the morning light. Later in the day, get several minutes of sun exposure outdoors. Don’t stare at the sun, but don’t use sunglasses to filter the light that enters your eyes, either. Finally, suspen the use of screens shortly after sundown. Sleep in a darkened bedroom, without nightlights or televisions on in your room.Take breaks (e.g., fast) from carbohydrates. Meal-skipping, intermittent fasting, low-carb eating, and a ketogenic diet will all support mitochondrial health by giving the mitochondria time to recovery from excess ROS intoxication. The natural processes of mitophagy and mitobiogenesis will upgrade the quality of your mitochondria — when they’re given time from excess carbohydrates.
Exercise after high carbohydrate meals. It doesn’t have to me a lot of exercise. The point is to give the energy produced from elevated blood glucose somewhere to go — e.g., to power body movement. Moreover, exercise stimulates mitobiogensis in the muscles, which wil help mitochondria handle largher glucose loads in the future.
Add magnesium-rich foods to your diet, or supplement with Epsom salt baths and oral magnesium. The central atom in chlorophyll is magnesium, so it’s generally a good rule of thumb to assume that green, leafy, chlorophyll-rich plants are good sources of magnesium. The problem is that modern agricultural practices has depleted soils of magnesium and promoted growth of cultivated vegetables for bulk mass, rather than nutrient density. As a consequence, green leafy vegetable contain less magnesium per unit volume than they did decades ago. Epsom salt soaks and magnesium supplements can help make up the difference.
Magnesium plays a critical role in mitobiogenesis, because it catalyzes over 300 metabolic reactions that are regulated by enzymes by mitochondria. That is, mitochondria are rich in magnesium because they require it for proper functioning.Practice deliberate cold exposure. Nothing accellerates mitophagy and mitobiogenesis as well as whole-body, cold-water immersion. The body reacts to cold exposure in many ways, including cold thermogenesis — both in shivering muscles and in non-shivering brown fat. When activated by temperatures that are cold enough, cold thermogenesis will clear glucose and triglycerides from the bloodstream and signal rejuvenation of mitochondria. The result is better enegertic function, increased insulin sensitivity, and a reduced risk of mortality that is sometimes described as younger biological age.
[1] Type 1 diabetes is a tragic auto-immune disorder in which the body attacks its own islet cells for reasons that are unfathomable. Once destroyed, the islet cells cannot be replaced. For example, islet cell transplants into Type 1 diabetics fail because the new islet cells are just as vulnerable to auto-immune attack as the old – even when the new islet cells are donated by an identical twin. Consequently, Type 1 diabetics rely on injections of exogenous insulin produced by genetically modified bacteria. Despite my objection to genetically modified foods, I harbor no moral objection to the genetic modification of bacteria to produce chemically human insulin. The technology saved my son the side effects of having to inject insulin extracted from the pancreas of pigs and horses, and I’m grateful for that.
[2] I’ve tried to avoid confusion by policing my use of these terms so that they are correct in the context that I use them. Wherever you object to my failure to make careful distinction, you’re welcome to call it to my attention so that I can correct it in an future edition of this book.
[3] Margulis was also known as Lynn Sagan, because she was married to the famous cosmologist and television scientist Carl Sagan at the time she published her seminal paper: Sagan L (1967). On the origin of mitosing cells. J Theor Biol 14, 225–274.
[4] Gray MW. Lynn Margulis and the endosymbiont hypothesis: 50 years later. Molecular biology of the cell. 2017 May 15;28(10):1285-7.
[5] The most important difference between prokaryotes and eukaryotes is that the DNA inside a eukaryote is protected within a nucleus. Eukaryotes have only one copy of their DNA, and so it makes sense that it should be afforded additional protections. By contrast, the prokaryotic origins of mitochondria mean that they have multiples copies of mDNA that just float around inside their larger organelle membrane and are more vulnerable to damage.