mitochondrial nutrients

Beyond Calories In and Calories Out

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Since the early 20th century, calories have been equated to health and energy. The assumption is that calories, no matter their composition, equal energy, and energy equals health. Strictly speaking, this is correct. The body will take whatever it is given, and to the best of its ability, convert it into cellular energy or adenosine triphosphate (ATP). That process produces heat and heat is the unit of change underlying the concept of calories. Mathematically, a calorie or kilocalorie (kcal), the unit used in food science, represents the heat or energy required to raise the temperature of 1 kilogram (kg) of pure water to 1° Celsius. This equation is used to calculate the heat content of food and determine the amount of heat energy produced as the food passes through the body. Another simple metric called the basal metabolic (BMR) is used to calculate the energy one requires to survive. From these two metrics, we get the calories in/calories out framework that dominates conversations about health and disease.

According to this framework, if the two numbers balance, we should have sufficient energy to meet the demands of daily living. If we consume more calories than we burn then, we should have excess energy, which can be used to increase one’s activity level or be stored as potential energy for use in the future. In today’s sedentary environment, it is usually the latter. Conversely, if we consume fewer calories than necessary, decrements in energy and weight loss should follow. In either case, energy is simply a matter of physics. Heat energy is transferred from one source – the food, to another – the body, or from the body to the environment at large, as one uses the energy in daily living and it dissipates.

This is the framework that has guided the medical profession, the food industry, and countless weight loss gurus for generations. To that end, it is of little to no concern what these calories are comprised of and very little thought is given to the endogenous processes underlying the generation of heat or energy. This framework allows us to represent health and illness mathematically. It is simple, recognizable, and easily understood, and perhaps that is why we hold dearly to it but is it accurate? What if there is more to this story? What if energy is not just a matter of heat transfer and what if the content of the calorie matters as much or more than the calorie itself? To answer that question, we need to determine what type of energy the body needs to survive and how that energy is derived.

What is Energy?

If energy is not a matter of calories, at least not in the sense that is portrayed, what is it then? In the body, energy comes in the form of ATP molecules, produced primarily by the mitochondria. In broad terms, ATP is the result of a series of reactions that combine oxygen with components of metabolized foods. Part of this process takes place in the cell but most of it takes place in the cell’s power plants, the mitochondria.

If all is going well, derivatives of fat, protein, and carbohydrates, the macronutrients contained in food, are shuttled into the mitochondria, through what is called the tricarboxylic acid (TCA) cycle (also called the Krebs or citric acid cycles), combined with oxygen, and through a series of reactions, collectively called oxidative phosphorylation (OXPHOS), produce ATP. From the oxidation of one glucose molecule, we get around ~30-36 ATP molecules. From one fatty acid molecule, we get over 100 ATP molecules, and from the amino acids, we get either substrates for the synthesis of other proteins, more glucose to metabolize and feed into the mitochondria (amino acids can be converted into glucose via gluconeogenesis), or another compound called pyruvate that may also be used by the mitochondria to make fuel or converted into lactate.

When things are not going as well or when quick energy is needed for certain functions, a number of extra-mitochondrial pathways, are used to break down the various macronutrient components to provide energy. There are two key pathways here. One is called glycolysis and the other is called the pentose phosphate pathway (PPP), which connects glycolysis with the TCA and OXPHOS and performs a few other important tasks like providing substrates for DNA and RNA synthesis. The PPP nets 1 ATP molecule per molecule of glucose, while glycolysis nets about 2 ATP molecules per molecule of glucose. A third pathway, used primarily in quickly replicating immune cells and cancer cells, involves shuttling glutamine, an amino acid, through the side door of the mitochondria to produce ~24 units of ATP per unit of glutamine. Severely stressed neurons use this pathway as well.

Which pathway is used to produce ATP may alternate according to to need, cell type, fuel type, micronutrient, and/or oxygen availability. Some cells metabolize a good portion of their energy in the cytosol using glycolysis while others rely almost exclusively on the OXPHOS in the mitochondria. This flexibility allows cells to adapt rapidly to changing circumstances. If one macronutrient is not available, energy is derived from another. When a micronutrient (vitamin or mineral) is not available, the products are diverted through other pathways, and when there is limited oxygen, glycolytic pathways will take over. All of this is meant to help the body metabolize different compounds and maintain energy homeostasis relative to environmental demands.

Different Energy Pathways for Different Cells

The body requires an enormous amount of energy to meet the demands of life. We effectively turn over our weight in ATP every single day. Every. Single. Day. That is absolutely remarkable. When we exercise, we produce even more – 0.5 to 1.0 kg per minute. Fully 95% of this energy comes from mitochondria, making mitochondrial fitness of the utmost importance. Many cells contain anywhere from 1000 to 2500 mitochondria and can represent from 25% to upwards of 60% of the cell volume. Accordingly, the average cell may use upwards of 10 billion units of ATP per day.

The production of ATP is critically important for survival and so its manufacturing of ATP is inherently dynamic and adaptable. The body will take whatever it is fed and turn it into energy using whichever pathway is available. So even when we feed ourselves garbage food, the body will do its best to manufacture some quantity of energy. The body does, however, have preferences. Importantly, different types of cells favor specific fuel types or pathways.

Skeletal muscles, for example, use fatty acids shuttled through the mitochondria for fuel when at rest but switch over to glucose, creatine, or lactate via glycolysis as exercise intensity and/or duration increase. Creatine, synthesized in the liver from glycine (and taken as a popular supplement in the athletic community), is part of a system that effectively recycles ATP in skeletal muscle during intense bouts of exercise. Lactate, originally believed to be a waste product, is actually an important fuel source. The ability to repurpose lactate, and metabolize it into ATP, whether via glycolytic pathways or via derivatives that will enter the mitochondria, is a major determining factor in forestalling fatigue for athletes and non-athletes alike.

You might be thinking, if glycolysis produces less energy per unit of glucose, why would the body choose to use it? Two reasons. The first is speed. Sometimes the energy is needed more quickly than can be provided by the mitochondria. So the body trades some capacity for speed. This occurs in fast-growing cells like the immune cells that need to replicate quickly during an infection. Similarly, high-energy situations like intense and quick bouts of exertion favor glycolysis. These are normal and adaptive. Secondly, glycolysis and its sister pathway, the PPP, also provide important components for cell building. If that is what is required, those are the pathways that will be used.

Unfortunately, glycolysis is also favored when the mitochondria are struggling. Here, molecules that would normally be shuttled into the mitochondria are diverted into other paths, and energy production is diminished. This is common in patients with metabolic disorders. The excess intake of sugars often paired with a lack of micronutrients overwhelms mitochondrial capacity, and as a result, much of the glucose remains in the cell and is either metabolized into what few ATP the cell can muster via glycolysis or shuttled towards other pathways that will act as waste management and expend rather than create energy. Cancer follows this pattern.

The continuously active heart cells require a huge amount of energy, approximately 6 kg of ATP per day to pump blood, most of which comes from the mitochondria. At rest, ~90% of the heart’s ATP comes from the oxidation of fatty acids in the mitochondria. During exertion, there is a slight shift in substrate preference and more glucose is used. Instead of a 90/10 split of fats to glucose, with activity, the split is closer to 60/40. In either case, these numbers show us that mitochondrial capacity and diet are incredibly important for heart health. Low fat, high carbohydrate diets, as have been recommended for decades, go against the fuel preference of a healthy heart. The result of this type of diet is evident in the cardiovascular disease associated with metabolic syndrome. With metabolic syndrome, which represents nothing more than dietary damage accrued over time, the mitochondria lose the capacity to metabolize fatty acids for ATP and instead must rely exclusively on glucose for energy. The resulting decrements in energy underlie many of the aberrant patterns in rate, rhythm, and pressure. The heart simply does not have the energy to pump effectively at rest but especially under stress. Importantly, with metabolic syndrome, dysfunction expands beyond the heart, and other cells will also lose the capacity to metabolize fatty acids, gradually shifting to a more glucose/glycolysis dominant metabolism.

The brain consumes a substantial amount of glucose to meet energy needs (5.6mg of glucose per 100g of brain tissue per minute), with neurons using up to 80% of that energy. While the brain represents only about 2% of the body’s mass, it consumes 20% of the daily energy budget. Since the brain and the nervous system effectively manage all aspects of survival, decrements in energy metabolism have deleterious effects not only on the range of behaviors typically attributed to the brain, thinking, memory, planning, speech, emotion, movement, and the like but also on the automatic or autonomic control of organ function. For example, the parts of the brain located in the back of the head, collectively called the autonomic system (the cerebellum and brainstem, together with the nerves that flow through the spinal cord to the various organs and tissues), are exquisitely sensitive to changes in energy availability. The brainstem especially, because it controls breathing and heart rate, the two most important functions for survival, requires massive quantities of ATP. When energy availability is compromised, heart rate, breathing, and other autonomically controlled systems become dysregulated leading to what is now called dysautonomia.

Although most of the brain’s energy is derived from the oxidative phosphorylation of glucose within the mitochondria, here too, lactate recycling, extra-mitochondrial pathways like the PPP and glycolysis also play a role. Additionally, as ketogenic diets have shown us, the brain may use ketones derived from fatty acids as a fuel source.

Even proteins may be used for brain fuel. This is a relatively new discovery and not widely appreciated, but a set of neurons in the hypothalamus called the orexin or hypocretin neurons (same neurons, different names), require amino acids to fire. Specifically, and in order of potency, glycine > aspartate > cysteine > alanine > serine > asparagine > proline > glutamine induce orexin firing. This is important because these neurons are the primary energy sensors in the brain. They are responsible for maintaining wakefulness, providing the motivation to eat, and monitoring brain energy levels as a whole. Mutations in these neurons are responsible for narcolepsy, but due to their energy-sensing role, any disruption in brain energy, may force sleep and induce anorexia. In other words, these neurons control survival functions that become disrupted when ill. Low concentrations of orexin/hypocretin lead to what is called ‘sickness behaviors’ – the behaviors that every organism exhibits when ill. These neurons are also involved in precipitating migraine implicating brain energy deficiency here too. Interestingly, unlike other neurons in the brain, where glucose spurs activity, in these neurons, glucose spurs inactivity, perhaps through associated inflammation. Glucose, particularly high glucose, will cause these neurons to stop firing, which may be perceived as excessive fatigue, an insatiable need for sleep, and when severe enough, coma.

Of interest, the most important amino acid for the proper activity of these neurons is glycine. Glycine is an essential amino required for protein synthesis and repair. It is also an excitatory neurotransmitter in its own right, affecting other neural systems. Glyphosate, the chemical used on virtually all commercially grown agriculture (and thus, consumed by all commercially grown livestock), is a glycine analog. That means that whenever we consume commercial foods where glyphosate-based herbicides are used liberally, we are substituting natural and endogenous glycine for a synthetic analog. This substitution has a long list of health-derailing effects. Another ill-effect to add to that list may be the inappropriate regulation and responsivity of the orexin/hypocretin neurons.

The Composition of Calories

The section above illustrates the necessity for providing a variety of whole and uncompromised foods to fuel the body and it should fundamentally shift how we perceive the energy capacity of different food types. The body requires a variety of fuel sources to function appropriately. From the calorie-focused perspective of energy, none of this matters. It is assumed that so long as there are ample calories, energy production will be maintained at sufficient levels. The makeup of those calories is inconsequential to ATP output. This is clearly incorrect. For even if we look only at the raw numbers of units of ATP per pathway, it is evident that the composition of the diet matters. Someone who eats a predominately carbohydrate-based diet will produce quantitatively fewer ATP molecules than someone whose diet derives the bulk of their calories from fats. Similarly, the ability to funnel macronutrient components through the mitochondria and to run OXPHOS will produce more energy than if one’s cells are stuck in the glycolytic pathways. When a diet is skewed towards one type of food, the pathways that rely on the other macronutrients will be impacted negatively and this, in turn, will affect the organs that prefer one type of fuel over another.

If we dig a little deeper and look at the composition of consumed carbohydrates and fats, there are even more differences to consider. For example, carbohydrates coming from refined sugars like high fructose corn syrup (HFCS) produce less ATP than those that come from whole and unadulterated grains, fruits, or vegetables. In fact, the metabolism of HFCS requires ATP rather than produces it, and as an added complication, a good portion of the metabolized products derived from HFCS never enter the mitochondria but are instead converted to triglycerides and stored as fat. Similarly, consumed fats that come from animal fats versus seed oils, differ in their ability to produce ATP. Soybean oil, an oil extracted from soybean seeds, not only incites inflammation and a host of other ailments, but it downregulates the enzyme that sits at the entry point to the mitochondria, effectively blocking glucose metabolism and shifting everything to glycolysis for a huge net loss in ATP production. Since all heavily processed foods contain both of these ingredients, consuming these products with any regularity diminishes, and likely damages mitochondrial function. The net result is poor energetic capacity.

And if we dig deeper still, we find that the thousands of chemicals used to grow, preserve, enhance, and package these products, leach nutrients, derail mitochondrial functioning, and in many instances, evoke mitochondrial cell death. Consuming these foods, as so many of us are inclined to do regularly (57% of kcal in the American diet is composed of ultra-processed foods), leads to poor mitochondrial function and limited energetic capacity. It is not just the processed foods that have become problematic though. Conventionally grown produce is less nutritious than what was grown a few decades ago before the adoption of glyphosate-based herbicides and the genetically modified plants designed to withstand these chemicals became so pervasive. As discussed previously, glyphosate-based herbicides like Roundup that are ubiquitous in conventional agriculture (1.8 billion pounds of glyphosate used annually, enough for 4 pounds per person per year), block glycine. These herbicides also chelate (remove) minerals from the soils and plants and from the humans who consume these products. Minerals like calcium, magnesium, zinc, and manganese, which, as we will see later, are critically important for mitochondrial function. Indeed, the original patents for glyphosate involved its industrial descaling capacity, exactly the mechanisms enacted in the human body. It should be noted though, that glyphosate is just one of the tens of thousands of chemical toxins we are exposed to daily, most of which have never been tested for safety but instead are assumed to be safe under the poor regulatory template called GRASgenerally recognized as safe.

Each toxin that we ingest (or breathe), requires an ATP-using response from the body, thus diminishing potential reserves by some quantity. One can imagine, how over time the repeated consumption of these types of products might fundamentally alter mitochondrial function and reduce ATP capacity. Importantly, since the gastrointestinal (GI) system provides the interface between consumed foods and the rest of the body and is responsible for the digestion, absorption, and metabolism of food-based nutrients and excretion of toxicants, reduced mitochondrial functioning e.g. reduced ATP in the GI system is doubly problematic. Not only is GI functioning disrupted and oftentimes damaged by these types of foods, but the ability to derive nutrition becomes impaired as well. It takes energy to make energy and it takes energy to extract and metabolize nutrients and excrete waste products. Commercial foods, while high in calories and non-caloric additives are low in energy. These foods lack actual nutrients and nutrients are what mitochondria need to make energy.

How Do We Fix This Mess

It should go without saying that we ought to eat better and avoid food and other toxins where we can, but the food landscape is such that this can be difficult, especially if one is already ill and reactive to many foods and/or other substances. In those cases, it is important to understand what it takes to make energy from food, determine what is potentially missing from your diet, and replenish accordingly. This is not easy and will take a fair amount of detective work on your part, but it is possible.

We briefly covered the macronutrients, here we will look into the micronutrients. Micronutrients are vitamins, minerals, and some metal ions. In generations past, before we sterilized the soils with chemicals and modified the plants to withstand those chemicals, one could consume a complement of these micronutrients so long as one had a reasonably balanced diet. It is here where the concept of calories made a little more sense when food was food and not some commercially derived concoction. That is no longer the case. The advent and escalation of herbicides, pesticides, and the slew of additives, preservatives and other noxious chemicals in the food chain have effectively stripped modern foods of nutritional capacity while retaining caloric content. This means, that for many people, supplements will be required. Which ones and what dosages, however, will vary significantly. For that reason, it is important to understand how the mitochondria work so that you may become your own expert.

Broadly, for foods to be metabolized into energy, for any macronutrients to enter the mitochondria and run OXPHOS, vitamins and minerals must be available to power the enzymes leading to and through the mitochondria. If there are insufficient vitamins and minerals both in general and relative to the concentration of macronutrients (high calorie, low nutrient foods) or demand (toxins, stressors, illness), the TCA cycle does not work, OXPHOS does not work well, the body has to shift to alternate pathways. With this shift, not only is ATP reduced but because these pathways burn dirtier, more endogenous pollutants, like reactive oxygen species (ROS), are released. The oxidative stress that ensues damages mitochondrial membranes, further taxing mitochondrial capacity. This damage simultaneously demands more energy to resolve while reducing the capacity to produce that energy. Over time, the ability to manufacture ATP becomes so disrupted and produces so much oxidative stress that the entire process of extracting and metabolizing foods into energy further damages the mitochondria. Eating the very nutrients the body needs becomes a stressor and the individual becomes stuck in a seemingly never-ending negative cycle of malnutrition causing more malnutrition with any attempts to rectify inducing negative reactions. This is the state I find many people with chronic illness in – in desperate need of nutrients but unable to consume them.

Let us look briefly at the micronutrients involved in deriving energy from proteins, carbohydrates, and fats. Below is a graphic from the book I co-authored with Dr. Derrick Lonsdale. While it focuses on thiamine, it lists many of the other nutrients required for mitochondrial metabolism. Notice that within each pathway, a variety of vitamins, minerals, and metal ions are necessary to power the multiple enzymatic reactions require to produce ATP. The B vitamins and magnesium, in particular, play an important role in the early phases of these processes.

Mitochondrial nutrients

If any of those micronutrients are missing or are in short supply, the enzymes requiring those nutrients will not work as efficiently and the capacity to produce ATP will decline. With that decline comes a slew of compensatory reactions that will reallocate resources based on energy availability. Those reactions frequently involve inflammation, altered hormone regulation, and other adaptive measures, as reduced energetic capacity is a signal to other mitochondria and other cells that something is wrong.

Nothing works without energy and energy is impossible without the vitamins and minerals that drive mitochondrial function. Not even respiration is possible. Cellular respiration, the most fundamental form of respiration, the activity that breathing itself, requires critical micronutrients. Oxygen cannot be used or trafficked appropriately creating a state of hypoxia. Hypoxia, I believe, is what drives most modern illnesses. So let us take a look.

Micronutrient Deficiency Driven Hypoxia: The Root of All Illness

Among the least well-recognized reactions to reduced nutrients is a type of hypoxia called molecular or pseudo-hypoxia. Here, unlike the typical obstructive hypoxia, nothing is blocking or preventing oxygen intake. What is missing are the micronutrients required to power key enzymes involved in oxygen utilization. Specifically, for cells to breathe and to utilize oxygen to produce energy, the mitochondria require adequate thiamine (vitamin B1), magnesium, and riboflavin (vitamin B2). Looking at Figure 1, you will notice that thiamine and its activating cofactor magnesium appear frequently throughout each of the pathways used to convert foods into energy. Indeed, they are what are called rate-limiting co-factors in these processes. Meaning that if their levels dip, everything else downregulates as well.

Importantly, thiamine, magnesium, and riboflavin, along with alpha-lipoic acid, are integral to the functioning of an enzyme complex called the pyruvate dehydrogenase complex (PDC). PDC sits atop the mitochondria and acts as a gatekeeper of sorts. With insufficient concentrations of these micronutrients, the metabolism of glucose into ATP is blocked. The metabolites of other macronutrients, after some processing also utilize the PDC as an entry point, and so they too will be blocked from entering the mitochondria. As a compensatory reaction, the mitochondria initiate a series of reactions that signal danger. Among them is the release of proteins called hypoxia-inducible factors or HIFs for short. Once released, HIFs then signal all of the other changes consistent with chronic illness like inflammation, hormone reregulation, altered immune responsivity, etc. These are meant to be short-term protective measures that reduce energy requirements and increase blood flow and oxygen to the cells. Unfortunately, because these are nutrient-driven reactions, they will not be resolved until the nutrients come back on board consistently. As a result, these patterns become entrenched, and therein lies the root of many chronic illnesses.

Symptomatically, early one and when this set of reactions is limited to specific tissues, injury and inflammation will appear regional to those tissues or organs.  The GI system, both because it sits at the interface between food consumption and nutrient absorption and because the microbes that inhabit the GI tract also require thiamine, will often show disruption first. The poor nutrient landscape not only impacts energetic capacity, disrupts peristalsis, and the movement of foods through the tract, but also shifts the microbial ecosystem towards more pathogenic microbes that adapt more easily to the nutrient-starved environment.

When nutrient deprivation goes on long enough and the HIFs become stabilized, not only do we see all of the compensatory reactions mentioned above, but when severe enough, we will see underlying molecular hypoxia manifest like a sensation that one cannot get enough oxygen, even though oximeter readings are perfectly normal. This is frequently referred to as air hunger.

Whatever the individual response, however, since mitochondria control life and death cycles at the cell level, ailing mitochondria that cannot manage these cascades effectively, die a messy, necrotic death that is highly inflammatory and immune reactive. What little intracellular ATP is available to power cell function is spit out of the cell and used as a danger signal to other cells. High levels of extracellular ATP are indicative of severe mitochondrial stress. When this happens, even less intracellular and intra-mitochondrial ATP is available to power basic survival functions, and importantly, to create more energy.

This begins the downward trajectory of chronic illness where one needs energy to make energy but simply does not have it; where one needs key nutrients to resolve the energy crisis but does not have the energy to metabolize those nutrients.

Resolution and Prevention

Ideally, we would prevent the downward trajectory of mitochondrial illness, but modern life, such as it is, presents innumerable threats to mitochondrial energetics. The biggest, of course, is poor diet. By focusing on the caloric content of foods, and the ease and speed at which we can prepare those foods, rather than their capacity to provide critical nutrients, we have missed the physiological purpose of eating – to provide energy to live and to function. In light of what is required to create energy from food, balanced macronutrients with an array of micronutrients, we must consider the composition of the foods we eat, especially when one is dealing with a chronic and seemingly treatment-refractory illness.

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This article was published originally on July 19, 2022. 

Mitochondria Need Nutrients

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One of the more common questions I get asked is which nutrients do the mitochondria need to function well? This is really two questions. The first involves which nutrients are involved in the enzymatic processes that allow the mitochondria to convert food to ATP and to manage all of the other tasks that they are responsible for like inflammation, immune function, and steroidogenesis. The second question applies specifically to the individual. It is a question of what he/she needs to be healthy. The answers to both are entirely different. While it is true that there are a set of nutrient co-factors involved in the mitochondrial machinery and these are necessary for mitochondrial function for everyone, which ones and how much of each an individual may need to support his or her health varies significantly. Moreover, although there are baseline minimum nutrient requirements that tell us where insufficiency diseases are likely to develop, what determines an individual’s health or disease is entirely dependent upon genetics, exposures, diet and lifestyle, and even day to day stress. Here, there is no one-size-fits all prescription for nutrient replacement and supplementation or even diet and exercise. This frustrates folks to no end and I think it is one of the reasons both patients and physicians are so reticent to look toward nutrient supplementation seriously as a therapeutic option.

Both the current model of medicine, and to a large degree, the way we approach nutritional therapies, relies very heavily on the silver bullet approach to health. If we’re honest with ourselves, so too do we. It is so much simpler to believe that if we just take X drug or vitamin in Y dose, all of our health issues will disappear and they will disappear at set rate that is linear and predictable. Unfortunately, this is not how the body works. While there is an internal chemistry that requires certain nutrients to function appropriately, that chemistry varies ever so slightly by genetics and is endlessly modified by life itself. There is no one-size-fit-all. There are no magic supplements. There is just your chemistry and your needs.

Since I have written repeatedly on the mitochondria and the reasons why nutrients are required for health, this post will not tackle those topics. Articles on those topics can be found on Hormones Matter with any number of search terms. This information can also be found in the book, Thiamine Deficiency Disease, Dysautonomia, and High Calorie Malnutrition, that I co-authored with Dr. Lonsdale. Here, since many have requested it, I just would like to present a graphic illustrating mitochondrial nutrient requirements. This is from Chapter 3 of our book. Use this as template to understanding your health.

Figure 1. Nutrient requirements for healthy mitochondria.

mitochondrial nutrientsA few things should be pointed out. First, while these nutrients are required by everyone for proper mitochondrial functioning, not everyone needs to supplement with each one, or even sometimes any of them, although that is becoming increasingly rare with modern dietary patterns. Secondly, notice how many times and where vitamin B1 (thiamine) appears in this chart. It is at the entry points of the entire system and at various junctures throughout. This suggests that among all of the nutrients required for healthy mitochondria, thiamine is particularly important. Unfortunately, it is the one nutrient that is so often ignored or missed in testing. Indeed, that is why we wrote the book. Thirdly, notice how many vitamins are required to process the food we eat into ATP. Contrary to popular opinion, we need more than simply empty calories. For the foods we eat to be converted into ATP, there are multitude of vitamins and minerals required that may or may not be included in sufficient density with the macronutrients we consume daily. Finally, not discussed in this chart, but discussed in great detail in the book, synthetic chemicals, whether in form of pharmaceuticals, industrial, environmental, or food production, damage the mitochondria. Some deplete nutrients directly, while others damage aspects of mitochondrial functioning that necessitate increased nutrient density for the enzyme machinery to work. Of course, underlying all of this, are the genetic variables that each of us brings to the table. These influence how well or poorly we metabolize any of these nutrients from the get-go. All of this combines to make nutrient therapies complicated.

What is not complicated, however, is that we need nutrients to function and so, no matter what else we do to improve health, if we do not address nutrient concentrations, we can never be well. Mitochondrial functioning demands nutrients, and thus, health demands the same. Nutrient deficiencies are not something we can override with a pharmaceutical. That being said, addressing nutrient deficiencies holds great promise for those seeking health. If you or someone you love experiences chronic and complicated illnesses that have been treatment refractory, consider healing the mitochondria by tackling nutrient deficiencies. You might be surprised at well this works.

We Need Your Help

More people than ever are reading Hormones Matter, a testament to the need for independent voices in health and medicine. We are not funded and accept limited advertising. Unlike many health sites, we don’t force you to purchase a subscription. We believe health information should be open to all. If you read Hormones Matter, like it, please help support it. Contribute now.

Yes, I would like to support Hormones Matter. 

This article was originally published on November 11, 2019.

The Myth of Nutritional Equivalence

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Over the last several months, I have been fascinated by the fuel preferences of the mitochondria in the different organs of the body. It seems that the mitochondria in each organ system have specific fuel preferences. The muscles like protein and carbs, the heart likes fatty acids, and the brain has all sorts of fuel preferences depending upon region and state of health. This is mind-blowing and contrary to medical textbooks on the subject. For as long as anyone has cared to address the fuel preferences of the mitochondria, an overly simplistic, black-box model has prevailed. The gist of which is the errant presumption that so long as there are sufficient calories ingested, no matter from where those calories originate, carbohydrate, protein, or fats, real food or processed garbage food-like products, the mitochondria will magically convert those foods into ATP, the energy used by our cells to perform the myriad functions of living. To some extent that is true, but woefully short of the real picture. Nevertheless, we have built an entire economy of medical thought supporting the ‘it just doesn’t matter’ model of feeding.

Based upon this equality of calories presumption, I have seen doctors ‘prescribe’ ice cream and other processed foods devoid of nutrients to children with growth deficiencies. Just as egregious, are the sugary chemical concoctions (Ensure, Boost, and the like) served to severely ill patients in any American hospital under the banner of ‘medical nutrition’. Admittedly, financial interests play a role, but undergirding those interests is the long held belief that calories are all that matter; a belief, that I would argue, we as a society, are all too happy to accept. It is a simple idea, one that doesn’t require much thinking, and best of all, lets us eat anything we want as long as the calories are balanced in our favor. Who among us has not convinced ourselves of the ‘healthiness’ of some low-calorie treat?

The Wonder of Fortified Foods

A similarly troubling assumption about food equivalency and one I see all too often is that enriched and fortified foods are nutritionally equivalent to native foods. This is certainly the reasoning behind the hospital protein drinks where calorie density plus fortification equals nutrition. But does it really? Do we really believe so strongly in the powers of modern industrial food chemistry that the foodstuffs we produce with seemingly infinite shelf lives, all manner of chemically derived flavor enhancers and colors, loaded with corn syrup, trans fats, and other delectable substrates are somehow converted into ‘healthy’ foods by the magic of fortification? Moreover, do we really believe that those processed substrates appropriately fuel the mitochondria?

Apparently so.

Just last week, some internet troll tried to argue that there was no such thing as vitamin or mineral deficiencies in modern America, citing food fortification programs as his example. Similarly, a few months ago I spoke at a conference on this topic and the physicians in the audience were incredulous about the idea of nutrient deficiencies for the same reasons. Even prominent researchers bang the food fortification drum. Consider this study.

“Only a small percentage of the population had total usual intakes (from dietary intakes and supplements) below the estimated average requirement (EAR) for the following: vitamin B-6 (8%), folate (8%), zinc (8%), thiamin, riboflavin, niacin, vitamin B-12, phosphorus, iron, copper, and selenium (<6% for all).”

It seems that we have solved malnutrition once and for all. Foodstuff fortification equals nutrition. You can have your Oreos and meet minimal nutrient requirements. End of story.

food fortification

Or is it?

Dig a little deeper and we see that we have done nothing of the sort. About the same study cited above, a secondary study said this:

“Without added nutrients, a high percentage of all children/adolescents had inadequate intakes of numerous micronutrients…”

“Among all age/sex subgroups, when considering only intrinsic nutrient intake from foods, approximately 25% to 100% had inadequate intakes of numerous nutrients, including vitamins A, D, E, folate, and calcium. Among females aged 14 to 18 years, approximately 23% to 92% also had inadequate intakes of thiamin, riboflavin, niacin, vitamin B-6, vitamin C, phosphorus, magnesium, iron, and zinc…”

“When nutrient intakes contributed from fortification were added, the %<EAR for vitamins A, D, B-6, C, the five enrichment nutrients, and zinc shifted sharply lower.”

Translation: most of the nutrients contributing to the presumption of nutrient sufficiency come from fortified food products and not actual food. So while fortification provides a bare minimum of nutrients and staves off outright malnutrition, can it be considered healthy? I don’t think so, but when we buy into the nutritional equivalence, calories in, calories out model of health, what we are saying is this:

fortified foods

Is nutritionally equivalent to this:

meat and vegetables

We are saying that it does not matter what types of foods we consume so long as they are fortified and so long as the calories balance. We are back to the notion that prescribing ice cream to spur growth in kids, fake ‘nutrition’ drinks for the ill and elderly, and all manner of other convoluted dietary machinations are okay, somehow healthy, and even, logical.

Of Fructose, ATP, and the Magical Mitochondria

If we take this logic one step further, we arrive at the door of that magical mitochondrial black box that will take any fuel we give it and turn it into ATP. Admittedly, to some degree that is true. No matter the origins of that fuel, mitochondria will break it down into its carbon skeleton and through a series of reactions produce ATP. That’s their job. The question, however, is at what cost. That is, are these food products the most efficient and desirable fuel substrates? More specifically, what is the energy cost to convert garbage food into ATP? Consider something as simple as fructose and how it moves through the glycolytic machinery:

“The flow of fructose into the glycolytic pathway gives the appearance that fructose is a benign fuel suitable for human (over)consumption; in reality, fructose’s conversion to fructose-1-phosphate drains ATP from the cell, promotes a dramatic inflammatory response, and leads to clinical features of insulin resistance, hypertension, and metabolic syndrome via several mechanisms, one of which is increased production of uric acid.” Alex Vasquez

Although the mitochondria will convert these fructose-dense foodstuffs into ATP, there are costs; costs that can only be accounted for if one moves beyond the black-box model of mitochondrial metabolism. And yes, I know, fructose comes in fruit and vegetables too, but where most folks get their fructose is not from fruit or vegetables but in the form of high fructose corn syrup, the staple sweetener in all processed foods.

Fortified Versus Real Food

The way I see it, there are at least two issues to consider when assessing the healthiness of food. Firstly, and as I mentioned previously, the mitochondria in the different organ systems require different macronutrients, one a well-balanced diet from real food would provide. In contrast, a diet derived from starchy, high fructose corn syrup sweetened and chemically processed carbs no matter how strongly fortified will never be able to match a well-balanced diet of whole foods.

Second, to get from macronutrient to ATP takes a whole host of nutrient co-factors, vitamins, and minerals, to power the enzymes responsible for this process. Take a look at the figure below from our book.  There are 24 vitamins and minerals needed to convert what we eat into ATP. More, if you consider all of the ancillary processes not charted here.

Mitochondrial Nutrients

mitochondrial nutrients

Even when the scales balance on our calories in, calories out model, they do not balance in the mitochondria and health depends entirely on the mitochondria. Diets heavy in processed foods not only lack the basic macronutrients, typically protein and good fats, but the minimal nutrients provided by these foods are neither sufficient to power the mitochondrial enzymes tasked with converting these products into ATP, nor are they sufficiently ‘nutritious’ to overcome the ATP costs of clearing all of the garbage that these products contain. This leaves us with decrements in ATP, and in a state of constant metabolic distress, which itself demands additional energy to resolve. It is a downward spiral to be sure; one where the use of ice cream or pseudo-nutritional drinks only hastens.

What do the Mitochondria Need?

A diet rich in real, organic foods is a good start. Look what happens when someone who is disabled by a chronic, neurodegenerative illness changes her diet. Health becomes possible.

Dr. Terry Wahls: Minding your mitochondria

Although a change in diet may not be all that is required, it is the foundation upon which health can be built; a foundation that is just not possible when ice cream is prescribed as nutrition.

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More people than ever are reading Hormones Matter, a testament to the need for independent voices in health and medicine. We are not funded and accept limited advertising. Unlike many health sites, we don’t force you to purchase a subscription. We believe health information should be open to all. If you read Hormones Matter, and like it, please help support it. Contribute now.

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This article was first published on August 13, 2018.

Are Your Mitochondria Stuck in Battleship Mode?

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As part of my work here, I am regularly confronted with desperately ill individuals who have seen dozens of physicians over the course of many years only to have their health continue to decline. Among the more frustrating aspects of this work is the failure of these physicians to assess and address the most basic aspects of health and healing. Namely, they fail to ask what the body needs to be healthy and whether the patient is getting those things. Of course, since evaluating these aspects health comes down to nutrition and exercise it does not align well with the practice of medicine, and if we are honest with ourselves, it is not something many of us want to deal with either. We want to eat what we want to eat and do what we want to do without regard to our health. Conventional medicine has capitalized on those sentiments, arguing persuasively for decades that a disease process is not real if all it requires to resolve is nutrients. Real illness requires medication, we now believe, having forgotten the very real nutrient deficient scourges like beriberi, Wernicke’s, pellagra, rickets, scurvy, and such.

Like most physicians, we have bought into the corresponding notions that fortification of foodstuffs assures that nutrient requirements are met and that in the land of plenty, where obesity reigns, malnutrition is rare. Neither is true of course, but belief in those myths absolves us of looking more closely at the chemistry of health and disease. For when we look at that chemistry, when we follow each of the altered signal transduction pathways, when look at the various patterns of deranged protein expression, and the myriad of genetic and epigenetic markers, we inevitably land at starving, inefficient mitochondria and the simple truth that they require nutrients to function; nutrient requirements that cannot be met by fortification alone and nutrient requirements, that if not met, lead to disease. When we dig a little deeper, we are also faced with a rather inconvenient truth that not only will pharmaceuticals not recover these deficiencies but they damage the mitochondria further. This does not accord well with the practice of conventional medicine and certainly does not fit into our busy, convenience-based lifestyles.

The Capacity to Survive

Among the more remarkable aspects of human physiology, however, is the capacity to survive all manner of illnesses and insults. We are supremely adept at adapting and surviving. We may not be living healthy, but we live. Mitochondria mediate these survival functions. They are responsible for converting the foods we consume and the oxygen we breathe into cellular energy (ATP).  With that energy, they regulate all aspects of basic survival at the molecular level, including survival itself – cellular respiration – but also things like inflammation, immune function, steroid hormone production, cellular life and death cycles, and whole bunch of other stuff. As one might expect, each of these functions is energy dependent.

Decrements in cellular energy, thus, elicit those survival mechanisms. If they are not resolved appropriately, when the threat persists, and/or when there is limited energy to face the threat, these normal responses lead to all sorts of tissue and organ dysfunction. It is this mismatch between the energy available and the energy required that leads to the persistence of not only the original illness, but because of the chronically activated survival cascades, leads to new and more complicated illnesses. On the one hand, decrements in ATP lead to things like inflammation and immune system activation – the normal, programmed and encoded survival cascades – but on the other hand, the survival cascades themselves lead to decrements in ATP, which in turn leads to more inflammation and immune reactivity. Without resolution, these cascades can easily become ingrained and ultimately lead to death. This suggests that energy availability is the key to health, or more specifically, that insufficient mitochondrial energy, and thus, impaired mitochondrial function leads to illness.

From Power Plant to Battleship: Mitochondrial Healing Cycles and the Necessity of Sufficient ATP

A recent paper suggests this is true. Just last month, one of the leading experts in mitochondrial function, put forth a compelling synthesis of research delineating what he called the mitochondrial healing cycles. Specifically, he demonstrated by what systems level mechanisms mitochondria maintain health or initiate and maintain disease. Dr. Naviaux argues that chronic illness is initiated by the “biological reaction to an injury and not the initial injury or the agent of injury itself.” He uses melanoma as an example, illustrating how it is not caused by the sun per se, but our biological, or more specifically, our metabolic (mitochondrial) response, to the sun. Chronic illness, he argues, becomes chronic only when there is incomplete healing of the original injury and/or when secondary injuries occur before primary injuries have healed. Illness, he suggests, is a multi-hit proposition.

To Naviaux, illness begins and ends in the mitochondria. Mitochondria are responsible for enacting what he terms the ‘cell danger response’ (CDR), the survival mechanisms that I spoke of earlier. There are three phases of the CDR:

  1. The initial inflammatory/immune response: “activation of innate immunity, intruder and toxin detection and removal, damage control, and containment.” He aptly describes this phase as a shift in mitochondrial energetics and function from power plant to battleship. ATP has to be diverted to fight the threat, initiate and maintain the characteristic inflammatory response. The reduction in ATP results in the characteristic fatigue we all experience at the beginning of an illness.
  2. Once the damage from the initial injury is contained, phase 2 begins. This involves replacing the dead and damaged cells as well as walling off any remaining damaged tissue that was not completely cleared in phase 1. Here stem cells are recruited and enter the cell cycle. Mitochondria in stem cells are critical for this phase, supplying the stem cells with ATP as well as key substrates to help with healing process. An interesting aspect of this phase, is that cell – cell communication ceases. There is no metabolic cooperation between cells as they are continuing grow and migrate. It is only when growth is complete and migration ceases that cell-cell communication reemerges.
  3. In phase 3, we get a return to “cell differentiation, tissue remodeling, adaptive immunity, detoxification, metabolic memory, sensory and pain modulation and sleep tuning”. Once the cells have been fully differentiated and re-educated, cell-cell communication reinstates and healing is complete.

The healing cycles are linear, sequential and ATP intensive. Each must be completed before the next can begin, before a secondary injury takes place, and each requires a continuous supply of ATP. Too many hits and/or too little ATP will derail healing. When we consider mitochondrial metabolism as the root cause of persistent disease, it is difficult not to ask what constrains the availability of energy and thus blocks the body’s ability to progress across each healing cycle.

Recovering Mitochondria: The Role of Nutrition

To answer this question, one has to look at how we produce ATP. Absent outright starvation, to get from food to ATP we need a few things: macronutrients and micronutrients or proteins, fats and carbohydrates along with vitamins and minerals. That’s it. Nothing fancy or complicated, just basic nutrition.

When we look at macronutrient consumption, one of the leading problems in western cultures is the high consumption of junk, carbohydrate-based foods. These foods, though they are often fortified with vitamins and minerals, come with far more sugar and other toxicants than the body can handle. Rather than being a net gain in energy, ultimately, become a net loss, both in macro, but especially, in micronutrients. Without sufficient micronutrients, none of the enzyme machinery, whether in the cytosol of the cell or in the mitochondria themselves, can perform the required functions that moves the macronutrient through the factory and produces ATP. Indeed, even the consumption of molecular oxygen requires the presence of vitamins and minerals. Absent those vitamins and minerals, a sort of cellular hypoxia sets in; one that activates inflammatory pathways, and ultimately, the shift in tale tell shift energy production associated with cancer known as the Warburg effect.

Conversely, because of decades-long advertising campaigns, most folks, but women especially, consume insufficient quantities of protein and fat. This skewed consumption of macronutrients places a high demand on the OXPHOS (oxidative phosphorylation) pathway of the mitochondria to produce ATP, while simultaneously not providing sufficient micronutrients to fuel the enzyme machinery to produce this ATP. It also increases the need for detox, while again, failing to provide adequate substrates to do. Moreover, if the diet is high in the staple sweetener high fructose corn syrup, in addition to everything else that becomes dysregulated at the mitochondrial level, the ability to covert fatty acids into energy, can be shut down entirely, conferring a metabolic inflexibility that is common in western cultures.

Along with issues with macronutrient consumption, large percentages of the population are deficient in one or more of the micronutrients required for healthy mitochondria. Individuals with chronic illness are severely deficient. The mitochondria require 22 vitamins and minerals in varying concentrations to convert the food we eat and the air we breathe into cellular energy or ATP (Figure 1.). Absent sufficient concentrations of one or more of those nutrients, mitochondrial function deteriorates and healing will not progress. Survival mode is all that can maintained.

mitochondrial nutrients
Figure 1. Mitochondrial Vitamins and Minerals

With Naviaux’s framework, it becomes clear that healing is an energy intensive process. The only way to boost energy is via good nutrition. Sure there are compounds that can override certain pathways within the mitochondria and, at least temporarily, provide additional energy, but if the core requirements for optimal mitochondrial health are not met, it is only a matter of time before initial benefits become problematic. (I should note that exercise is also critical for healing the mitochondria. Exercise forces mitochondrial biogenesis among other important processes.) The questions that physicians and individuals with chronic illness should be asking are:

  1. What is required for health?
  2. Is this patient or am I getting those things?

Unless and until those aspects of health are addressed, chronic illness will persist because the mitochondria simply do not have the resources to progress through the healing cycles. There are no short cuts here.

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More people than ever are reading Hormones Matter, a testament to the need for independent voices in health and medicine. We are not funded and accept limited advertising. Unlike many health sites, we don’t force you to purchase a subscription. We believe health information should be open to all. If you read Hormones Matter, like it, please help support it. Contribute now.

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This article was published originally on October 17, 2018. 

Thoughts on Inflammation, Vaccines and Modern Medicine

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One of the core components of an HPV vaccine adverse reaction inevitably includes some degree of seemingly unexplainable but observable brain inflammation and white matter disintegration. The brain inflammation falls under a number of different names and diagnoses, some are regionally specific, cerebellar anomalies for example, while others demarcate a more diffuse injury including, acute disseminated encephalomyelitis (ADEM), myalgic encephalomyelitis (ME), sometimes known as chronic fatigue, multiple sclerotic (MS) type lesions and, the newest and perhaps more prescient among them, a set of conditions designated as Autoimmune/Inflammatory Syndrome Induced by Adjuvants or ASIA that denote chronic inflammation both centrally and peripherally relative to vaccine adjuvant exposure.

Is the Brain Immune Privileged?

Despite the observance of brain inflammation in many post HPV vaccine victims, many practitioners, and indeed, the FDA and CDC, seem loathe to recognize that an aluminum lipopolysaccharide adjuvanted virus vector might induce a neuro-inflammatory response, leaving patients with little recourse post injury. The difficulties attributing brain inflammation to a vaccine reaction stem from a long held belief that the blood brain barrier is stalwart in its protection against peripheral trespassers.  The brain has long been considered, ‘immune privileged’ having little to no communication with peripheral immune function. Indeed, the perceived impenetrableness of the blood brain barrier is so extensive that brain-body separation might as well be complete, with a brain in bottle and a decapitated body.

Logically, we know this cannot be true. There must be crosstalk between the immune systems of brain/central nervous system and that of the body. How else could we survive if the two modalities were segregated so completely? It turns out, that logic may be prevailing. A decade of research suggests that the long held notion brain immune – privilege is completely and utterly incorrect. Indeed, the immune system not only guides early neurodevelopment (and so mom’s immune function matters) but communicates and affects brain morphological changes chronically. Likewise, signals from the brain continuously influence peripheral immune function.

The immune system appears to influence the nervous system during typical functioning and in disease. Chronic infection or severe illness may disrupt the balance of normal neural–immune cross-talk resulting in permanent structural changes in the brain during development, and/or contributing to pathology later in life. The diversity, promiscuity, and redundancy of “immune” signaling molecules allow for a complex coordination of activities and precise signaling pathways, fundamental to both the immune and nervous systems. 

It should not be surprising then, that nutrient status and toxicant exposures in the periphery, in the body, affect central nervous system function and are capable of inducing brain inflammation and vice versa. And yet, it is; perhaps even more so than any of us realize.

Re -Thinking Brain Inflammation

When one reads through the definitions, research and case reports of ADEM, ME, MS or other instances of brain inflammation, the notion that biochemical lesions in the periphery are linked to observed neuro-inflammatory reactions is far from center stage. Nevertheless, if we can accept the premise what happens in and to the body does not stay in the body, then we can begin to re-frame our approach to brain inflammation. Specifically, we can look at inflammation more globally and ask not only what triggers inflammation, but allows inflammation to persist chronically, regardless of its location. If there is an on-going peripheral inflammatory response, is it not prudent to suspect that a similar response might be occurring within the central nervous system, even if our imaging tools are not yet capable of visualizing the inflammation; even if it is too premature to observe demyelination, neuronal, axonal swelling or other telltale signs of chronic brain inflammation?  I think it is.

Vaccine Adjuvants: A Pathway to Brain Inflammation

With the HPV vaccine, and indeed, any vaccine, the deactivated viral vectors come with a cocktail of additional chemical toxicants and a metal adjuvant to boost the recipient’s immune response, as measured by the increase in post vaccine inflammatory markers. It is believed that without these adjuvants (and data back this up), the recipient’s immune response is insufficiently activated to merit ‘protection’ against the virus. The strength or size of the immune response is then equated with success and protection.

By this equation, an excessive immune response that continues chronically and is eventually labeled ‘autoimmune’ as innate systems begin to fail, is in some way not a failure or side effect, but an example of extreme success; the larger the immune response, the stronger the vaccine. And so, skewed as this observation may seem, within the current vaccine-paradigm there can be no ‘side-effects’, not really. By design, there should be inflammation, even brain inflammation; the more the better. Also by design, metal, lipid soluble, adjuvants cross the blood brain barrier and directly induce brain inflammation. To say vaccines don’t or somehow couldn’t induce brain inflammation is ignorant, if not, utterly negligent, and quite simply, defies logic. Again, for prudence and safety, shouldn’t we assume that an inflammatory reaction in the body might also ignite some concordant reaction in the central nervous system?

Why Aren’t We All Vaccine Injured?

What becomes apparent though, is even with exposure to the most toxic brew of vaccines, not all who receive vaccines are injured, at least observably. (I would argue, however, even those who appear healthy post vaccine, had we the tools to observe brain inflammation more accurately, would show a central inflammatory response, at least acutely, and likely, progressively). So what distinguishes those individuals who seem fine post vaccine, particularly post HPV vaccine, from those who are injured severely and sometimes mortally?

More and more, I think that the fundamental differences between vaccine reactors and non-reactors rest in microbial and mitochondrial health. Indeed, all vaccines, medications, and environmental toxicants damage mitochondria, often via multiple mechanisms, while altering microbial balance. Whether an individual can withstand those mitochondrial insults depends largely upon a balance struck among three variables: 1) heritable mitochondrial dysfunction, genetic and epigenetic; 2) the frequency and severity of toxicant exposures across the lifetime; and 3) nutrient status. Those variables then, through the mitochondria, influence the degree and chronicity of inflammation post vaccine. With the HPV vaccine in particular, the timing of the vaccine, just as puberty approaches and hormone systems come online, may confer additional and unrecognized risks to future reproductive health.

Mitochondria and Microbiota

The mitochondria, as we’ve written about on numerous occasions, control not only cellular energy, but cell life and death. Every cell in the body, including neurons in the brain, require healthy mitochondria to function appropriately. Healthy mitochondria are inextricably tied to nutrient concentrations, which demand not only dietary considerations but balanced gut microbiota. Gut bacteria synthesize essential nutrients from scratch and absorb and metabolize dietary nutrients that feed the mitochondria. Indeed, from an evolutionary perspective, mitochondria evolved from microbiota and formed the symbiotic relationship that regulate organismal health. Disturb gut bacteria and not only do we get an increase in pathogenic infections and chronic inflammation, but also, a consequent decrease in nutrient availability. This too can, by itself, damage mitochondria.

When the mitochondria are damaged, either by lack nutrients and/or toxicant exposure, they trigger cascades of biochemical reactions aimed at conserving energy and saving the cell for as long as reasonably possible. When survival is no longer possible, mitochondrial sequestration, and eventually, death ensue, often via necrosis rather than the more tightly regulated apoptosis. Where the mitochondria die, cells die, tissue dies and organ function becomes impaired. I should note, as steroid hormone production is a key function of mitochondria, hormone dysregulation, ovarian damage and reduced reproductive capacity may be specific marker of mitochondrial damage in young women.

Mitochondria and Inflammation

Mitochondria regulate immune system activation and inflammation and so inflammation is a sign of mitochondrial damage, even brain inflammation. Per a leading researcher in mitochondrial signaling:

The cell danger response (CDR) is the evolutionarily conserved metabolic response that protects cells and hosts from harm. It is triggered by encounters with chemical, physical, or biological threats that exceed the cellular capacity for homeostasis. The resulting metabolic mismatch between available resources and functional capacity produces a cascade of changes in cellular electron flow, oxygen consumption, redox, membrane fluidity, lipid dynamics, bioenergetics, carbon and sulfur resource allocation, protein folding and aggregation, vitamin availability, metal homeostasis, indole, pterin, 1-carbon and polyamine metabolism, and polymer formation.

The first wave of danger signals consists of the release of metabolic intermediates like ATP and ADP, Krebs cycle intermediates, oxygen, and reactive oxygen species (ROS), and is sustained by purinergic signaling.

After the danger has been eliminated or neutralized, a choreographed sequence of anti-inflammatory and regenerative pathways is activated to reverse the CDR and to heal.

When the CDR persists abnormally, whole body metabolism and the gut microbiome are disturbed, the collective performance of multiple organ systems is impaired, behavior is changed, and chronic disease results.

Reducing Inflammation

Instinctively, we think reducing inflammation pharmacologically, by blocking one of the many inflammatory pathways, is the preferred route of treatment. However, this may only add to the mitochondrial damage, further alter the balance of gut microbiota and ensure increased immune activation, while doing nothing to restore mitochondrial and microbial health. In emergent and acute cases, this may be warranted, where an immediate, albeit temporary, reduction in inflammation is required. The risk, however, is that short term gains in reduced inflammation are overridden by additional mitochondrial damage and increased risk of chronic and/or progressive inflammation. The whole process risks becoming a medical game of whack-a-mole; a boon to pharmaceutical sales, but devastating to those who live with the pain of a long-standing inflammatory condition.

In light of the the fact that damaged mitochondria activate inflammatory pathways and that vaccines, medications and environmental toxicants induce mitochondrial damage, perhaps we ought to begin looking at restoring gut microbial health and overall mitochondrial functioning. And as an aside, perhaps we ought to look at persistent inflammation not as an autoinflammatory reaction, but for what is it, an indication of on-going mitochondrial dysfunction.

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This post was published originally on Hormones Matter on September 22, 2014.