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Jun 1, 2022

Understanding Fatigue and Mitochondrial Energy Production

by Dr. Dan Kalish

I’ve spent the last six years studying the intersection of metabolomics (the study of metabolism) and genomics (the study of genes as they express specifically in terms of health consequences). This lands you right in the middle of mitochondria. Mitochondria control aging and play a major role in determining when we die. Mitochondria create the energy we burn, and so when not working properly, can cause symptoms like fatigue. Mitochondrial treatments and treatments of fatigue can be clinically impactful and change a patient’s life. In functional medicine, we often focus on restoration of mitochondrial energy production. 

The treatment of fatigue takes on great importance in any functional medicine clinic because just about every patient we work with has fatigue as a top complaint. Understanding fatigue and mitochondrial energy production takes you on a journey into biochemistry and cell physiology -  if you really want to grapple with the metabolomics and genomics of it all. There are, of course, many causes of fatigue ranging from simple, like iron deficiency, to complex like thyroid hormone imbalances or neurotransmitter problems. 

Mitochondrial energy production is one of the more common and complicated underlying causes of fatigue. Other symptoms that can accompany fatigue can include brain fog or memory problems, cardiovascular issues, weight gain or blood sugar handling problems. When one aspect of metabolism is disrupted, it’s common that others fall out of sorts too. I’d like to cover the basic aspects of mitochondria health focusing on where we see problems appear most frequently, and get you thinking about treatment options.

One can test for and treat the following issues:

  • Beta oxidation (burning of fatty acids)
  • Glycolysis (burning of carbohydrates)
  • Protein metabolism (burning of amino acids)
  • Citric acid cycle
  • Electron transport chain
  • Oxidative stress
  • Glutathione reserves

There’s more, but these are the basics for testing and treatments; problems in each of these areas can have slightly different consequences that can often be determined based on patient history and symptoms. Gathering this info, you can then combine lab data and genomics to round out your assessment skills leading to clinically effective treatment programs for fatigue and other common mitochondrial symptoms like weight gain, sugar cravings, cardiometabolic issues and the like. 

Beta oxidation is the process by which we grab fatty acids (30% or so from the diet and 70% or so made by your body) and turn the fat into fuel for our cells. It’s an extremely complex series of pathways that usher fatty acids from the cytosol into the mitochondria, and it’s regulated by a series of enzymes. The more complex pathways like beta oxidation are prone to genetic defects and are also susceptible to problems when key nutrients are missing. In the case of beta oxidation your cells require riboflavin (also known as vitamin B2) and carnitine. Vegans are particularly susceptible to carnitine deficiencies all of which can be determined by measuring organic acids that elevate when our fat burning metabolism gets bogged down. 

There are at least three organic acids that will reveal beta oxidation defects. Adipate, suberate and ethylmalonate. Interestingly, these three organic acid markers  were originally developed to detect severe disease states of metabolism that can occur in newborn babies. With major genetic problems known as inborn errors of metabolism babies can face potentially life threatening health consequences. The scientific literature on these inborn errors of metabolism is extensive and carnitine and B2 are used as treatments for these children. These health concerns are found soon after birth in those infants that have the full blown genetic diseases of metabolism. Many of us however have very mild genetic defects referred to as SNPs (single nucleotide polymorphisms) that can impact beta oxidation. It’s the exact same mechanism, just a much milder form of it. 

Alternatively, you can also be deficient in B2 or carnitine and have no genetic component to the problem. With more advanced levels of lab interpretation skills, you can begin to differentiate those with basic nutrient deficiencies and those with the mild form of the genetic disorders. The fascinating thing about all this is the ability to repurpose a type of testing designed to detect life threatening defects in newborns, those inborn errors of metabolism, and apply the same technology to both adult onset genetic metabolic disorders as well as more run of the mill nutrient deficiencies. Those with straight nutrient deficiencies will get better quickly and not need to be treated for too long; Those with a potential genetic component may require higher dosages for longer periods of time. 

By working at developing your lab interpretation skills, you can help a lot of folks out there that have a wide range of problems. 

Glycolysis, like beta oxidation, has a series of key enzymes that are prone to not working well. Pyruvate and lactate levels can be assessed on organic acids testing to determine how well a person’s ability to break down glucose is working. Problems in these pathways are the early warning signs of insulin resistance. High pyruvate and high lactate mean that your body can’t use carbs properly. This in turn leads to problems with the cells using insulin properly and a later build up of fat in the liver, and can end in diabetes or metabolic syndrome with high triglycerides, high cholesterol and high risk of a heart attack or stroke. Pyruvate dehydrogenase and lactate dehydrogenase are two of my favorite enzymes, really second only to succinate dehydrogenase which is part of the citric acid cycle and electron transport chain (google them all please, they are quite something to look at). These enzymes all contain lots of amino acids meaning they are prone to all kinds of potential genetic variations that can render them less than perfect in their processing of carbs. 

Sugar cravings, weight gain, high body fat percentages, problems with insulin, inflammation, oxidative stress, LDL’s and so on come about after long periods of elevated pyruvate and lactate. It’s worth testing these on every new patient. Hey, it’s all on the same lab report; Organic acids covers all the markers we’re discussing here!

So let’s assume you can perfectly metabolize fats and carbohydrates. The next things that can go wrong are the citric acid cycle and electron transport chain. Now we are going up a major level, maybe more like ten levels of complexity. The citric acid cycle has enzyme after enzyme, each one complex, difficult for your body to make and prone to error. And then once you get to the bottom of the process, the electron transport chain takes mitochondria to an ultra high level of sophistication and precision function. 

The deeper the complexity, the more room for error. And yes you’ll find text books on inborn errors of metabolism that are solely about the citric acid cycle enzymes that can go bad in newborn babies. Same same with CoQ10 genetic defects. And once again, one can have adult onset genetic disorders of metabolism or a simple deficiency of the associated nutrients required for these biochemical pathways to operate. 

Your body has to take the breakdown product of carbs or fats and convert them into acetyl CoA which then enters the citric acid cycle. In order to get through this obstacle course of enzyme conversions you need all kinds of B vitamins. B1, B2, B3, B5…It’s hard to properly convey the critical role of B vitamins in all this. They are like the diamonds in a diamond necklace. B vitamins get looked over and aren’t always seen as the major metabolic players that they are. 

Low B vitamins equals fatigue and mitochondria dysfunction. Treatment with B vitamins seems almost too easy, but getting the dosages right can prove to be a challenge. It takes practice to make it all work. You can, and should, use organic acids lab testing to ascertain best dosage ranges, suffice to say without lab tests and retesting you’ll likely underdose patients on key B vitamins and, believe it or not, that is enough to cause a major catastrophe. 

Lab interpretation skills take a good year or two to develop; one has to test and retest patients to see the patterns emerge. What you’ll find in many cases, is an initial test demonstrates magnesium and CoQ10 and B vitamin deficiencies, and with treatment, you’ll see consistent success. Follow-up testing is key, and interpreting pre and post tests gets your lab skills up to another level altogether.

Ok, next we need to address the electron transport chain. This is the part where your mitochondria (somehow) sling electrons from one complex to the next. Going from Complex I to Complex II to Complex II to Complex IV. In this process, the flow of electrons pushes protons over the mitochondrial membrane, once enough protons build up, they flow back down through Complex V which spins around like a water wheel and helps facilitate the final stages of ATP production, which are magnesium dependent. The fact that your body can take one electron at a time and push them along these various mitochondrial membrane bound proteins is mind numbing. One cortical neuron at rest puts out 4.7 billion ATP. That’s not per minute or hour, that is every single second! It’s not possible to comprehend the speed at which this happens. The way the electrons move along requires an escort with a substance called CoQ10. CoQ10 takes one electron at time along this transport chain, how it can go back and grab a single electron, then move it over then go grab another one, is, again, hard to comprehend. 

A lack of CoQ10 would by definition end all of this, and quickly.

And by the way magnesium is also required for all this to work.

And so finally we get to oxidative stress and glutathione. Well worth waiting for. 

As your mitochondria produce energy they produce free radicals too. The more ATP you make the more free radicals are created. This is not necessarily bad, but it’s not good either. It’s necessary. Kind of a necessary cost of making ATP. In a perfect world, you would have enough antioxidants in your body to handle the free radicals that are a natural byproduct of energy production. This requires something called vegetables and fruit. If you make a lot of ATP and don’t eat a lot of antioxidants from vegetables and fruit, you end up with mitochondrial damage from excess oxidative stress. 

This is very common in endurance athletes who crank out tons of ATP and don’t eat well enough to offset the free radicals. This can also happen if you are exposed to excessive environmental toxins (which we all are these days). Sadly, breathing, drinking and just existing in the toxic world we have created exposes us and our mitochondria to environmental toxins which can easily damage mitochondrial enzymes. 

Seems succinate dehydrogenase is particularly susceptible to this type of damage, which is sad. Again, google succinate dehydrogenase and look at the images of its structure. It’s quite the protein. Beautiful but I guess not that tough.  The research of Dr. Joseph Pizzorno demonstrates that environmental toxin exposure is a larger factor in metabolic damage than poor diet or lack of exercise, which is quite something to consider. 

Bottom line here is a circular type of situation, high levels of oxidative stress lead to mitochondrial damage and mitochondrial energy production leads to oxidative stress. It’s an issue. And to wrap things up, glutathione is perhaps the key antioxidant in these various systems. Glutathione levels can change rapidly (our bodies can’t quickly adjust our vitamin A or vitamin C levels - other key antioxidants - on their own). Glutathione can be increased moment to moment as needed. 

So again, in a perfect world, if you have adequate glutathione reserves, and your mitochondria need the support of antioxidant protection to make more energy you can raise up your glutathione and things work out. If you don’t have adequate glutathione reserves, then mitochondrial energy production will drop off substantially. Your body can sense that with the lack of glutathione in the system, making ATP will make you worse because making ATP will generate uncontrolled free radicals that will damage and destroy cells. Your body does every thing it can in terms of compensation to avoid cell death. So rather than making more energy it will drop energy production to promote cell survival. 

This drop off is called a hypometabolic state or mitochondrial retraction. Your body will slow down mitochondrial function, and over time will decrease the actual numbers of mitochondria present in your tissues. This is categorically bad. But it’s a compensation, not a mistake or error. It’s a calculated sacrifice. Fewer mitochondria means less oxidative stress, but it also means destruction of mitochondrial populations. This causes deep states of fatigue. 

A damaged metabolism can be repaired over time. For this, we use free form amino acids in considerable dosages, B vitamins, CoQ10, PQQ, carnitine and a decent amount of support for glutathione using glycine and NAC. All this works surprisingly well, even in more advanced states of mitochondrial decline. Over the years of doing this work I’ve come to appreciate the restorative powers of the human body, as the old saying goes, “the power that made the body heals the body”. Whatever you believe that power to be, it’s quite something when given half the chance to operate properly again. All this takes some highly advanced lab interpretation skills and some follow up testing but it can be done, slowly but effectively.

This may sound a bit overwhelming at first, but with a year or two of concentrated training and implementing these types of lab-based protocols you’ll become an expert at rebuilding mitochondria, and be well positioned to help thousands of patients solve their fatigue issues throughout your career.

Dr. Dan Kalish

Dr. Dan Kalish

Founder of the Kalish Institute
Dan Kalish, DC, IFMCP, is founder of the Kalish Institute, an online practice implementation training program dedicated to building Integrative and Functional Medicine practices through clinical and business courses.