Persistent or “mystery” fatigue is one of the top conditions I treat in my functional medicine practice. It’s real, it’s extremely common, and sadly it’s very misunderstood in both conventional and alternative medical disciplines.
Fatigue is also one of the most challenging conditions to unravel because there are so many contributing factors. Sure, this is the case for most chronic conditions, but treating fatigue is very much like peeling back a really big onion. When you get one cause sorted out another tends to reveal itself (which is why evidence-based diagnostics are so very important!).
I’ve written about many of these causal factors before like intestinal hyperpermeability, thyroid disease, nutrient deficiencies, hormonal imbalance, and mood disorders.
However, there’s another causal factor that really isn’t talked about enough in traditional or integrative medical circles: and that’s the role mitochondria play in fatigue and fatigue-related conditions.
Now, if this seems like a heady topic and you can’t remember what the heck mitochondria is or what it does, stick with me! I’m going to make this super easy and FUN to understand plus include my best tips on optimizing mitochondrial function and energy.
A crash course in mitochondria: your cell’s energy manufacturing division
If you’re familiar with the ins and outs of mitochondrial function, then you can skip this section. But, for everyone else here’s a quick reminder/crash course.
Mitochondria are specific cell components known as organelles, found in nearly every cell of your body. They’re really cells within cells that serve a number of essential functions throughout your body’s organs and systems. But they’re best known for their role in creating the majority of your usable energy, known at ATP (adenosine triphosphate). 
Mitochondria are also involved in things like insulin secretion, neurotransmitter synthesis, heat production, production of specific enzymes (like CoQ10!), and calcium homeostasis. 
There are volumes more we could discuss on the many roles mitochondria play in sustaining human life and health, but for the purposes of how they relate to fatigue, there’s your bare-bones crash course.
Due to the obvious connection between mitochondrial function and energy levels, mitochondrial dysfunction has been studied in a number of fatigue-related conditions, which we’ll touch on today.
Note, there exists a set of conditions known as Mitochondrial Disease, which are caused by mitochondrial failure. These conditions are the result of either inherited or spontaneous mutations in mtDNA or nDNA which can lead to altered function in the mitochondria. These conditions are typically diagnosed in childhood, are considered chronic, and can be very serious. Although fatigue is a hallmark symptom of Mitochondrial Disease, this disease is not the focus of today’s article.
How low-grade inflammation influences mitochondria, nutrient reserves, and energy production
It’s been well established that inflammation is at the heart of chronic disease and autoimmune conditions. 
This includes fatigue-related diseases like Chronic Fatigue Syndrome and also mystery or persistent fatigue.
So it should come as no surprise that inflammation also influences the health and function of mitochondria.
Here’s how that works:
Inflammation of any kind, but especially chronic inflammation, increases the energy needs of your immune cells in order to keep you healthy.
To meet this need, your immune cells’ mitochondria switch to a less efficient but faster acting form of energy production known as aerobic glycolysis.
This is fine for a short-term issue, like if you fall and sprain your ankle or have a bout of flu. However, if your immune cells are forced to rely on aerobic glycolysis for an extended period of inflammation (aka: chronic inflammation caused by intestinal permeability, chronic stress, autoimmunity, etc.) this could lead to a reduction in available nutrients resulting in less energy for your organs and systems.
In my practice, this often shows up in lab work as nutrient deficiencies or trends toward deficiencies. Yes, this type of thing shows up with other conditions too like genetic mutations and methylation issues, for example.
However, I begin to suspect a mitochondrial component when specific nutrients are lacking in a patient who eats a healthy, nutrient-dense diet, taking high-quality supplements, etc., and/or when dietary/supplement changes aren’t making a difference in their energy levels.
What specific nutrients am I talking about? Vitamins and co-factors that play a role in mitochondrial function such as: vitamin E, CoQ10, riboflavin B2, niacin B3, l-carnitine, lipoic acid, and acetyl-l-carnitine.
The big takeaway here is: chronic inflammation can vastly inhibit your cells’ ability to efficiently produce the energy you need to feel well and balanced.
CoQ10 and fatigue (the most studied mitochondrial enzyme/nutrient)
Chronic inflammation is a problem for mitochondrial function and overall health because it causes the body to break down. Some experts liken it to “rusting” because it’s largely caused by free radicals (unstable molecules) which target and damage healthy cells.
However, free radicals can only cause lasting cell damage when they are left unchecked by their natural predators: antioxidants.
And when it comes to mitochondrial protection, CoQ10 is their antioxidant enzyme superhero! Not only does it protect mitochondria and their cells from free radical damage, it also plays an essential structural role in the production of ATP.
Thus, CoQ10 deficiencies or insufficiencies are common in those who suffer from fatigue…but they don’t stem from dietary issues!
Unlike other types of antioxidants like vitamins A, C, and E the vast majority of CoQ10 is produced within the body. Thus, deficiencies or trends toward deficiency point to a problem with cellular synthesis. Which can stem from things like CoQ10 depleting drugs like statins, chronic and neurodegenerative diseases like thyroid, heart, liver, and kidney disease, diabetes, cancer, and fibromyalgia , ,  and the aging process.
Fortunately, CoQ10 supplementation can be effective for helping restore reserves, improve chronic conditions, and support healthy energy.
Mitochondria and diabetes and metabolic disease
Metabolic diseases including Type 2 diabetes, insulin resistance, and prediabetes are common causes of fatigue in patients (and often people don’t even realize they have blood sugar issues).
In relation to mitochondrial function, there has been plenty of research showing a connection between insulin secretion/glycemic control and mitochondrial health.
For example, mitochondrial dysfunction is a well-known cause of Type 2 diabetes. There’s even a type of diabetes known as Mitochondrial Diabetes, which is often mistaken for Type 1 or Type 2 diabetes or hyperglycemia.
So how exactly do mitochondria affect metabolic health?
Since mitochondria affect nearly every cell in the body the implication of dysfunction to the endocrine and metabolic systems involved in blood sugar balance is vast. Let’s look at a couple specific examples of this connection.
When mitochondria become dysfunctional, they can affect the pancreatic beta cells which has been implicated in the pathology of chronic metabolic disease. Plus, the generation of reactive oxygen species (which can oxidize cells) from mitochondria may interfere in insulin signaling in muscle, contributing to insulin resistance.
The most important thing to understand here is that fatigue often indicates a blood sugar issue that can be rooted in mitochondrial dysfunction.
Even if your fasting glucose test comes back “normal” that doesn’t mean you don’t have an issue. This is why I always insist on an HbA1c test, which measures glucose levels over a period of months…instead of just a few hours. And increasingly in my practice, I have started using Continuous Blood Glucose monitoring to better assess glucose status.
How to support your mitochondria and restore precious energy
Although your mitochondria were probably the last thing on your mind when you woke up this morning, I hope you’re starting to see how important they are to supporting healthy energy and preventing fatigue.
But what can be done to support the health of your mitochondria and their essential nutrients and co-factors? Fortunately, a lot!
Here are some therapeutic measures I recommend to my patients:
- Intermittent fasting which has been shown to help slow mitochondrial aging 
and stabilize blood sugar levels 
- Reduce chronic stress to prevent chronic disease. Get more tips in:Emotional Detox Strategies Every Woman Should Know.
- Exercise! Specifically High Intensity Interval Training (aka: HIIT) which has been shown to significantly improve glycemic control and lower insulin levels and enhance mitochondrial volume.
- Eat anti-inflammatory foods while avoiding trigger foods including lots of fresh vegetables and fruits, grass-fed meats, healthy fats (which means unrefined oils like olive, avocado, and coconut).
- Exposure to cold temperatures, like going outside on a cold day or splashing cold water on your face, has been shown beneficial for increased expression of mitochondrial biogenesis, a process that improves mitochondrial mass and glucose uptake in muscle.
- A ketogenic diet has been shown to enhance mitochondrial respiration and cellular energy production while helping control insulin.
- Resveratrol for enhanced antioxidant protection and increased mitochondrial biogenesis 
- CoQ10 supplementation, as noted above.
- Lipoic Acid to reduce oxidative stress and improve mitochondrial function.
- Nicotinamide Riboside, a lesser-known form of vitamin B3 (a mitochondrial co-factor) that may help improve insulin sensitivity and support mitochondrial biogenesis. 
- NAC (n-acetylcysteine) has been shown protective to mitochondrial biogenesis and the effects of oxidative stress aka: free radical damage. 
- L Carnitine provides the fatty acids your mitochondria need to produce energy. 
- Curcumin offers superior antioxidant protection to cells and mitochondria while helping prevent mitochondrial dysfunction, increase ATP levels and mitochondrial mass., , 
As always, I strongly recommend having a conversation with your doctor aboutthe best pharmaceutical-grade supplement brands. CoQ10, for example, comes in a variety of forms and delivery systems that vary widely in quality and efficacy.
Ready to get to the root cause of your fatigue?
As we talked about at the beginning, getting to the root cause of fatigue is like peeling back a really big onion. Which is why I always recommend partnering with a functional and integrative medicine physician who specializes in fatigue.
As doctors, we have the appropriate diagnostic tools to help uncover those multifaceted causal factors, plus the best of conventional and integrative medicine tools to help you heal for good.
If you’d like to work with me and are located in the great state of Texas, click here to learn more about becoming a patient.
Outside of Texas? Check out the Institute for Functional Medicine’s practitioner finder to locate a qualified certified functional medicine physician in your area. And check out my book Bloom, where we do a deep dive into the pathogenesis of fatigue along with a step-by-step program to help you heal.