Strengthening Your Mitochondria to Help Fight Fatigue
By Dr. Debby Hamilton, MD, MPH
By Dr. Debby Hamilton, MD, MPH
Fatigue is one of the most common symptoms seen in primary care.1 Symptoms of fatigue can be acute during illness, or chronic, lasting months to years. The important thing with fatigue is to uncover the biological cause.
One of the primary causes of fatigue is mitochondrial dysfunction. The mitochondria provide our cellular energy, and when they are not functioning optimally, our cells’ energy production is low, leading to the symptoms of fatigue.
Mitochondria are small organelles that exist inside cells for the primary purpose of creating energy in the form of ATP. All of our food is composed of the macronutrient’s carbohydrates, proteins, and lipids. These macronutrients are broken down into acetyl-CoA, which begins the Krebs or Citric Acid Cycle.
This cycle feeds into the mitochondrial membrane, where oxidative phosphorylation takes place. Oxidative phosphorylation and the formation of ATP happens through the electron transport chain. The electron transport chain has complexes I-V, which are critical for forming ATP. This energy production requires multiple cofactors that, if low, could decrease the production of ATP. There are numerous steps in the development of energy, beginning with the breakdown of the macronutrients, where dysfunction can happen in the mitochondria.
Fatigue is the primary symptom seen in mitochondrial dysfunction.2 As a non-specific symptom, fatigue can be described differently by patients.
It can include prolonged recovery after exercise called post-exertional fatigue, decreased endurance, mental and physical fatigue, and overall lack of energy.2 Since the brain contains a large number of mitochondria, cognitive dysfunction such as poor memory and attention can be signs of mitochondrial weakness. Other non-specific symptoms such as chronic pain and weakness, can also be explained by mitochondrial dysfunction.3 Classical mitochondrial dysfunction from genetic causes will exhibit similar symptoms but is often diagnosed earlier in life and has multiple organ involvement.4
A normal part of the production of energy from mitochondria is the production of free radicals, which makes mitochondria the primary producer of free radicals in the cell.3 Because of this function, mitochondria are at high risk for oxidative stress damage from an excess of free radicals. The damage can impact both their DNA and their cell membrane. Antioxidants within the cell, such as Vitamin E and CoQ10, work to neutralize free radicals.* A decrease in CoQ10, which is common with aging and chronic disease, has been associated with oxidative stress and mitochondrial damage.5
Inflammation along with oxidative stress is common in many chronic issues. Part of our immune response is the recruitment of immune cells and the release of cytokines creating free radicals to combat an immune threat.
If the immune reaction becomes chronic, there can be an increase in free radical production resulting in the development of oxidative stress from inflammation, then leading to mitochondrial dysfunction.
One of the common questions from practitioners is how do I test for mitochondrial dysfunction? Classic mitochondrial disease was diagnosed by muscle biopsy, which is invasive and not needed for acquired mitochondrial dysfunction.
Mitochondrial syndromes can be diagnosed with genetic testing often done in childhood when children present with multiple organ systems impacted early in life. Mitoswab is a genetic test done by a cheek swab which has been a good addition to diagnosing mitochondrial disease and dysfunction. It evaluates complexes I-IV of the electron transport chain, which can help identify support such as supplementation of CoQ10.
Both blood markers and organic acid urine test markers can be helpful in identifying mitochondrial dysfunction. Blood tests include a complete metabolic panel, pyruvate, lactate, creatinine kinase, CoQ10, free and total carnitine, plus an acylcarnitine profile and amino acids.
In my experience, these markers are more often positive with more severe long-standing mitochondrial weakness and dysfunction. A functional medicine organic acid urine test, in my experience, is helpful for identifying mitochondrial dysfunction earlier.
Since oxidative stress plays such a large role in the development of mitochondrial dysfunction, measuring markers of oxidative stress can be useful additional information. Although there are many research markers of oxidative stress, available markers that can be helpful are F2-isoprostanes, markers of lipid peroxidation, and 8-hydroxy-2-deoxyguanosine (8-OHdG), a marker of mitochondrial DNA damage.
Supporting mitochondrial function involves supporting multiple different pathological issues.
The mitochondrial membrane is sensitive to damage by oxidative stress. This membrane is made from phospholipids, including phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylinositol (PI), phosphatidylserine (PS), and phosphatidic acid (PA), as well as phosphatidylglycerol (PG) and cardiolipin (CL).6 Both phosphatidylglycerol and cardiolipin are unique to mitochondrial membranes.6 When the mitochondrial membrane is damaged, it releases cytochrome C leading to apoptosis of the mitochondria.7 Supplementing phospholipids may help support a healthy mitochondrial membrane and is an important component of supporting healthy mitochondrial function.*
The production of energy by the mitochondria is a multi-step process involving cofactors, including many vitamins and minerals. These nutrients, including NADH, CoQ10, and carnitine, can be low from poor dietary intake, aging, and increased metabolic needs from illness. Decreased levels of both CoQ10 and carnitine have been seen in mitochondrial dysfunction. Pyrroloquinoline quinone (PQQ) has been found to be important in energy production by the mitochondria and acts through cell signaling pathways.8 PQQ supplementation has been shown to improve mitochondrial dysfunction markers.8 NAD/NADH and many of the B vitamins are important cofactors in mitochondrial energy production.9 Supplementing with a combination of B vitamins, NAD/NADH, CoQ10, PQQ, and carnitine along with the phospholipids is a good foundation for supporting mitochondrial health.*
Finally, we know that antioxidants neutralize free radicals which can be damaging to the mitochondria.* Several antioxidants are helpful for removing free radicals in the mitochondria and include vitamin C, vitamin E, and alpha-lipoic acid. Vitamin C protects from oxidative stress by entering the mitochondria.*10
When used together, alpha-lipoic acid (ALA) and vitamin E in animal studies show improvements in the mitochondrial electron transport chain.11 Adding antioxidants may help support mitochondrial function when combined with targeted mitochondrial nutrients and phospholipid support.*
Mitochondrial dysfunction is common, resulting in symptoms such as fatigue, pain, weakness, and cognitive dysfunction. Mitochondrial issues can be identified through testing and mitochondrial health may be supported through a multi-faceted approach involving a range of nutrients to support the phospholipid membrane, supply targeted cofactors, and provide antioxidants to reduce free radicals and oxidative stress.*