Integrative Medicine

6 Habits and the 7 Best Supplements to Improve Mitochondrial Function

By Kim Crawford, M.D. Last updated: March 23, 2021
6 Habits and the 7 Best Supplements to Improve Mitochondrial Function

Mitochondria are the key to energy and health

Mitochondria are involved in many vital processes in human cells, including energy production, fatty-acid oxidation and the Tricarboxylic Acid (TCA) cycle, calcium signaling, , apoptosis (cellular death) and heat production. However to simplify things lets talk about energy and longevity which is what their function translates to for practical purposes. And to help this occur, we can review the health practices, along with the best supplements to improve mitochondrial function.

  • Why do we want well-functioning mitochondria?
  • What happens when mitochondria malfunction?
  • What about mitochondrial function and aging in general?
  • Mitochondria boosting health practices
  • Mitochondrial specific exercise
  • CoQ10
  • Alpha lipoic acid
  •  PQQ
  • L-carnitine
  • D-ribose
  • Phospholipids
  • NAD
  • Miscellaneous supplements
  • Final words

Mitochondria: Why do we care?

First, let’s discuss the “energy part.” Mitochondria  produce Adenosine Triphosphate (ATP). In the cell, the energy in the form of ATP is produced in two ways: in the cytosol as a product of glycolysis, and in the mitochondria as a product of oxidative phosphorylation. The substrates, in the form of fatty acids and pyruvate, are oxidized via fatty acid β-oxidation and the TCA cycle respectively. The Nicotinamide Adenine Dinucleotide (NADH) and flavin adenine dinucleotide (FADH2) produced by these reactions are used by the electron transport chain to generate ATP. Just remember from this complex discussion of energy production that you need ATP and you need NAD+/NADH to make that ATP so you feel as if you have enough energy.

Proper mitochondrial functioning is crucial for every enucleated cell in a body. A number of diseases are characterized by dysfunction of muscular or neural systems or metabolic reactions. All these diseases and pathophysiological conditions are developed against a specific genetic background, together with environmental factors.

Mitochondria produce energy as ATP (adenosine triphosphate) which your body then uses to fuel your daily activities. Some cells have more mitochondria than others. Your brain, muscles and heart cells are full of mitochondria. Putting diseases and aging to the side: you want your mitochondria working at full strength to keep your energy levels up, your brain sharp and your muscles and heart at their peak performance. The creation of new mitochondria (mitochondrial biogenesis) is needed for optimal aging which we now call our health span. Not to be repetitive but always remember, this is mandatory to keep your energy levels at peak. It’s also a part of what’s needed to protect you from oxidative stress. As you would predict, mitochondrial dysfunction tanks your energy and contributes to numerous physical ailments.

Mitochondrial Dysfunction and Disease

Mitochondrial dysfunction, characterized by a loss of efficiency in the synthesis of ATP, is a characteristic of aging, and essentially, of all chronic diseases. Loss of function in mitochondria can result in the excess fatigue and even other symptoms in just about every chronic disease you can imagine.  These conditions include neuro-degenerative diseases, such as Alzheimer’s disease and Parkinson’s disease and Amyotrophic Lateral Sclerosis.

Metabolic syndrome, heart disease, and diabetes are all associated with mitochondrial dysfunction. Metabolic syndrome is a group of conditions which combine hypertension, hyperglycemia, abdominal obesity and abnormal cholesterol or triglyceride levels. Metabolic syndrome greatly increases the risk of cardiovascular disease, stroke and Type two diabetes. There are numerous reports mentioning mitochondrial dysfunction and lower oxidative capacity in patients with Type two diabetes compared with healthy individuals.

The cardiovascular system strongly depends on mitochondrial function. Cardiomyocytes (heart cells) have very high mitochondrial content in order to produce the necessary ATP, and mitochondrial dysfunction inevitably leads to the development of cardiovascular diseases.

There is now increasing evidence of mitochondrial dysfunction in Alzheimer’s Disease, Parkinson’s Disease, Huntington’s disease, and Amyotrophic lateral sclerosis. Even some psychiatric conditions, such as autism spectrum disorders, schizophrenia, and bipolar mood disorders are included.

In addition, mitochondrial dysfunction plays a significant role in the inflammatory response in acute human pathologies. Systemic Inflammatory Response Syndrome (SIRS) is a pathological state with a systemic immune reaction to severe damage, including ischemia, acute pancreatitis, trauma and sepsis.

Autoimmune diseases such as rheumatoid arthritis, Crohn’s disease and systemic lupus erythematosus all are characterized by mitochondrial failure. Of course, truly fatiguing illnesses, such as CIRS (mycotoxin and mold illness and Chronic Lyme), Chronic fatigue syndrome, Fibromyalgia, and Gulf War Syndrome have mitochondrial near-failure as a prominent component. Lastly, as you might predict, cancer and chronic infections round out the list of disorders. If you have any one of these disorders, you will need to  improve your mitochondrial health and function in order to recover.

Mitochondria and Aging

A number of age-related processes (e.g. “normal aging of the brain”) are associated with mitochondrial dysfunction, so most of the popular aging theories take this into account. The mitochondrial theory of aging posits that the accumulation of damage to mitochondria DNA promotes the  process of cellular aging of both humans and animals. The theory claims that there is a  vicious cycle involving the accumulation of damage in mitochondrial DNA which then leads to more oxidative damage due to defects in the mitochondrial respiratory chain. Let’s say that this theory is true. What then can we do to save our precious mitochondria and therefore slow the aging in our cells and help prevent diseases?

Mitochondrial health practices

Eating an anti-inflammatory diet is one of the easiest ways to improve mitochondrial function. Polyphenol-rich foods such as blueberries, red and purple foods (e.g. raspberries and purple cabbage) and many fresh green foods are high in healthy mitochondrial-boosting polyphenols. Using intermittent fasting methods such as timed eating and intermittently “going keto” are also mitochondrial boosters.

Heat shock proteins produced by extreme cold or extreme heat are great for your mitochondria. Cold exposure is an easy way to give your mitochondria a boost. Studies have demonstrated benefits with “ice jackets”, facial submersion, and ice baths. Even cryotherapy tanks! And “ice swimming.”  Based on what I personally find tolerable and affordable, you can get enough of a boost by doing the following. At the end of your daily hot shower, just turn the temperature to cold for 30 seconds. It is mostly quite invigorating!

Far-infrared saunas are another way to generate heat shock proteins.  A FIR is a great investment in your health, as it is also a great way to do a bit of a detox.

Meditation and yoga also boost your mitochondrial output.

Ten minutes of direct sunlight is great for a burst of mitochondrial activity. Conversely, most data suggests that fluorescent lighting puts a damper on ATP production and mitochondrial biogenesis. The data is rather murky when it comes to EMF’s, blue-blocking glasses and so on, but it’s something to watch, as there seems to be some correlation between better health and less high-level EMF exposure, as well as less blue light exposure.

Exercising For Mitochondrial Health

Many types of exercise are mitochondria-healthy. Walking is great. Running is great. Weight training is great. Yet, the very best type of exercise for your mitochondria is high-intensity interval training. This doesn’t need to be complicated, but do get medical clearance if this is a new activity for you. Do you know how to do a burpee? Do burpees until you’re short of breath. Then catch your breath and do it again. Repeat this a total of 6 times if you can, less if you can’t.

You can do HIIT outside, too of course. If you have access to a track, great! If not, use a treadmill if you’re inside or run in your neighborhood if you’re outside. Sprint one lap. Or a half of a lap. Whatever gets you short of breath. Then, walk until you catch your breath and you can even lie down on your back for faster autonomic neurological adaptation for up to 90 seconds if you need that long to catch your breath. I do this in our lap pool and it’s far more fun than simply “swimming laps” to me.

Now, lets discuss the best supplements to improve mitochondrial function.

The best supplements to improve mitochondrial function

I see people perk right up within (literally) 24 hours of proper mitochondrial supplementation. If someone has a chronic and/or fatiguing illness or are just suffering from age-related mitochondrial failure, supplementation absolutely works. It sure beats energy drinks which end up causing adrenal issues and potentiating energy problems.

Here are the mitochondrial supplements that have been studied and proven effective.

Co-Q 10

CoQ10 is an essential electron carrier in the mitochondrial respiratory chain. In other (more complex) words, CoQ10 passes electrons between NADH-ubiquinone oxidoreductase,  succinate-ubiquinone oxidoreductase or succinate-cytochrome C oxidoreductase. You can now just forget you read that and rub your eyes. Basically, CoQ10 can be found in both oxidized (ubiquinone) and reduced (ubiquinol) forms, and the conversion between these oxidized and reduced states allows it to act as a cofactor of enzymatic reactions via the transfer of electrons.

CoQ10 is a critical part of the mitochondrial oxidative phosphorylation system. Over ten well done studies show that supplementation with this vitamin-like antioxidant compound in individuals with reduced CoQ10 levels results in increased energy production and reduced fatigue. The most dramatic results are in in those individuals with degenerative diseases. Here are some examples.

In studies using Alzheimer’s disease models, CoQ10 administration significantly delays brain atrophy and characteristic β-amyloid plaquing. In a 4 month clinical study on around 100 Alzheimer’s patients who took an oral mixture of vitamins E, C, CoQ10, and α-lipoic acid, the group receiving supplementation showed significant reductions in oxidative stress markers and subsequent DNA damage.

Individuals with Parkinson’s disease tend to show increased levels of oxidized (and by definition: damaged) CoQ10.  They also have significant increases in markers of oxidative stress and damage in their brains, which is partially reversible with CoQ10 administration.

One last important clinical note: recall that the heart is filled with mitochondria which are partially powered by CoQ10. If you are taking a statin drugs, please be aware that they deplete your body of CoQ10, so supplementation is a must.

Alpha-lipoic acid

ALA is a potent fat and water soluble antioxidant vitamin. It is also a metal chelator (helping to remove iron, copper, mercury and other heavy metals). It is also a fairly decent anti-inflammatory supplement. Clinically, α-lipoic acid has been used mostly to help treat complications associated with diabetes such as neuropathies and vascular (blood vessel)  complications. It also improves cognitive (brain) and mitochondrial function, adding to the evidence linking oxidative damage to mitochondria and cognition. The use of α-lipoic acid for chronic fatigue syndrome (CFIDS) has not yet been studied in controlled clinical trials. However, it is widely used in “fatigue regimens” (200-600 mg) as a way to both support mitochondrial function and reduce oxidative stress.

Despite its various potentials, the therapeutic efficacy of ALA is reduced due to its “pharmacokinetic profile”. Data shows that ALA has a short half-life and bioavailability (only about 30%) due to degradation in the liver and chemical instability in the stomach. The R isomer of ALA (R-lipoic acid) shows better pharmacokinetic parameters, including increased bioavailability as compared to the S isomer, ALA. Translated: just use R lipoic acid or a double dose of alpha lipoic acid for approximately the same results.

PQQ

Pyrroloquinoline quinone (PQQ) is  contained in fruits and vegetables such as kiwi fruit and green peppers. It has received a lot of research attention in the past several years. PQQ can reduce reactive oxygen species (ROS) levels and improve apoptosis (death) of tumor cells. PQQ protects tissues by regulating the redox (electron transfer) reaction. Moreover, PQQ protects overall tissue function by improving the mitochondrial function of the liver, neurons and other important tissues. It can also reduce atrophy in mouse skeletal muscles.

PQQ decreases oxidative stress (production of ROS) and inflammation which, by definition will protect mitochondria. It also increases mitochondrial biogenesis which is the formation of new, young-acting mitochondria. It is neuroprotective, too. Here’s how. Recall that you have read about GABA versus glutamate or inhibitory (relaxing) versus excitatory (too stimulating) neurotransmitter activity. We want more GABA than glutamate, plain and simple. Too much glutamate damages brain cells. PQQ protects neurons by preventing the long-term over-activation of the glutamate (NMDA) receptors, which results in toxic excitotoxicity of neurons. This over-stimulation of brain cells is associated with many neurodegenerative diseases and seizure disorders.

Recall again that you have the largest concentration of mitochondria in your brain, heart and skeletal muscles. The brain “wins” pound for pound by a little edge, which is why you feel tired after using your brain all day. With this in mind, remember that when we protect the brain, we’re protecting brain mitochondria. PQQ protects the brain (to a certain extent) against neurotoxicity induced by mercury and other potent toxins such as mold mycotoxins. Lastly, it too helps to prevent the accumulation of amyloid tau and beta proteins associated with Parkinson’s and Alzheimer’s diseases.

Acetyl-l-carnitine 

Acetyl-l-carnitine is a naturally occurring fatty acid transporting amino acid. L-carnitine supplementation has long been studied and then used in many mitochondrial dysfunction disorders. These disorders are also characterized by low concentrations of serum l-carnitine levels such as heart disease, diabetes, kidney disease and overwhelming infections.

An important cellular longevity function of l-carnitine has been to increase the rate of mitochondrial oxidative phosphorylation (ATP production) that declines with age. A  study where old rats were fed acetyl-l-carnitine resulted in the reversal of age-related decreases in l-carnitine levels, an increase in fatty acid metabolism, and an increase in mitochondrial activity. Acetyl-l-carnitine also reverses the age-related decline in muscle mitochondria.

Clinical studies show that L-carnitine supplementation may also be useful in alleviating fatigue symptoms in hypothyroid patients, especially in those younger than 50 years and those who have hypothyroidism after thyroidectomy for thyroid cancer. Note: L-carnitine is the nomenclature used for many clinical studies, but due to l-carnitine’s ability to increase TMAO, experts suggest that all human supplementation be done with acetyl-l-carnitine.

D-ribose

We know that D-ribose has documented positive mitochondrial effects for those who are genetically d-ribose deficient. It’s a popular bodybuilding supplement which “hardcore” bodybuilders credit as being helpful with their with muscular fatigue. Studies have looked at neurodegenerative diseases such as Multiple Sclerosis and ALS with promising results. Due to these studies, I decided to use it in a protocol on a dog named Charlie. Charlie is a very beloved and smart standard poodle, belonging to a favorite patient of mine. The patient (another M.D.) contacted me, quite distraught that his dog had received the diagnosis of degenerative myelopathy or “doggie ALS” as I  found upon doing some research. Charlie, it seemed, couldn’t get himself up off the floor. The same mitochondrial problem has been identified in both dogs and humans. So, I got to work on Charlie’s protocol.

I calculated doses of supplements based on Charlie’s 48-pound weight. I recommended a mitochondria-boosting ketogenic diet. Then I added ALA, ALC, CoQ10, PQQ, and NAD (discussed below) as well as some d-ribose powder. I had my patient add some antioxidant powder to Charlie’s food, too. “Why not”, I thought. My patient said that 24 hours after Charlie started his regimen he was noticeably stronger, up and walking and even playing! The patient’s Veterinarian was astounded and has gone on to use my protocol on other dogs. Now, let’s give an honorable mention to another concoction.

Phospholipids

Mixtures of probiotic, phospholipid, and antioxidant preparations have shown some clinical promise in fatiguing illness. This mixture is made using antioxidant powders, probiotics and phosphatidylserine. The bulk of the studies have been with patients who have fibromyalgia and/or chronic fatigue syndrome (CFIDS).

NAD

NAD is now the big news, thanks largely to the research by Dr. David Sinclair and his best-selling book, “Lifespan.” Recall the mentions throughout this article about the  conversion of NAD+ to NADH, and vice versa, as essential reactions in creating ATP. Recall that ATP is cranked out by mitochondria, and give cells (and you) energy. Therefore NAD and it’s substrates are crucial for cellular energy, mitochondrial biogenesis and it turns out; cellular longevity. All that remains to be seen, is proof positive that one “form” of NAD is superior to another. Here’s some of the data.

Oral NADH supplementation can reduce symptoms in patients with chronic fatigue. One study on patients with chronic fatigue syndrome treated participants with micro-encapsulated, oral NADH or a placebo for a month’s time. 8 of 26 study participants (about 1/3) responded positively with increased well-being and energy levels to the NADH compared with 2 of 26 (8%) in the placebo group.

This supplement also shows promise for neurodegenerative disorders such as Parkinson’s and Alzheimer’s  diseases. The increase in measured NADPH levels correlates with a marker for aging: an increase in telomere length.

NAD will stimulate the SIRT1 pathway which is notably dysfunctional in those with metabolic syndrome, diabetes and more. When you stimulate the SIRT1 pathway, you lower leptin levels, making it again possible to lose weight, improve blood sugar, cholesterol and triglyceride levels, and in fact, all aspects of metabolic syndrome.

Taken orally, NMN (nicotinamide mononucleotide) is rapidly absorbed and converted to NAD+. In numerous studies, supplementation with NMN increases NAD+ biosynthesis, suppresses age-related fatty tissue inflammation, enhances insulin secretion and it’s action, improves overall mitochondrial function, and in the brain, it improves mitochondrial as well as neuronal function. In animal studies, it extends lifespan. In fact, NMN given to mice does quite a bit. Before I discuss NMN, let me give a shoutout to nicotinamide riboside- also converted to NAD+. As well as NMN? We don’t know, and the research continues. Meanwhile, we have a lot of data from mice studies.

Orally administered NMN is rapidly converted to NAD+ in mice. NMN has been shown to enhance energy metabolism and physical activity, suppress age-associated weight gain, improve insulin sensitivity and even improve ocular function. It improves mitochondrial metabolism and prevents age-related negative changes in gene expression. In mice bred to be obese or diabetic, NMN improved both the action and secretion of insulin.

NMN also protects the mouse heart from ischemia and/or reperfusion injury. It restores skeletal muscle mass in aging mice. Of special interest to those of us who treat many patients with brain issues, it has been shown to slow cognitive decline in a mouse model of Alzheimer’s disease, by improving the survival of neurons, improving energy metabolism, and reducing oxidative stress. It may also help maintain the integrity of the blood brain barrier.

NMN also probably suppresses the increase in systemic inflammation associated with aging-based on the studies which show that it lowers adipose tissue inflammation associated with age. In fact, surprisingly enough, older mice appear to be more responsive to NMN, in comparison with younger mice.

Some studies appear to suggest an increase in blood vessel formation called angiogenesis with artificially increased NAD levels for prolonged periods of time. This is why, despite the fact that I use a lot of NMN and intra-nasal NAD in my clinical practice, I have patients take intermittent breaks from it, and will do so until more data is available on this phenomenon.

Additional supplements with much promise

Studies are increasingly showing that mitochondrial illnesses are fueled by oxidative stress; implicating the use of antioxidants such as natural vitamin E and NAC (the precursor to glutathione) as well as glutathione as additional treatment considerations. We know that the sirtuin pathways are boosted by resveratrol and ECGC-green tea extract; implying  mitochondrial benefit. Branched chain amino acids, vitamin D, and creatine are all pro-mitochondrial health supplements as well, despite being poorly studied for this particular issue. Finally, there is emerging data for mitochondrial health with berberine, magnesium threonate, selenium and even immune-boosting melatonin. B vitamins are likely involved as well. It appears that the more useful a supplement has been proven to be (vitamin D as a prime example), the less it is studied for other, more complete benefits.

Final words

In any good health regimen, you want to eat an anti-inflammatory diet and take a few supplements. It makes sense to take vitamin D and a high antioxidant power or supplement for many reasons, including mitochondrial health. At this juncture, if you are healthy, and have specific goals in mind, you might choose, let’s say, some acetyl-n-carnitine if you are lifting weights, or some PQQ if you have a family history of neurodegenerative disease. And currently, if you have metabolic syndrome, SIRT pathway issues or fatiguing illness, it seems prudent and helpful to take NMN and/or NAD intra-nasal spray. Yes, IV NAD is beneficial, but I am “not a fan” of this current craze of “drip bars” and feel that consumers are being, quite frankly, ripped off by this trend, when alternative routes of administration can be utilized.

 

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