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How to Boost Mitochondrial Health


The powerhouse of our cells, mitochondria play a central role in energy metabolism to drive cellular function and basically every biochemical process in the human body.

One of the most important of these processes that occurs within the mitochondria is oxidative phosphorylation, which provides the body with the energy it needs to function in the form of adenosine triphosphate (ATP). Mitochondria also have important roles in apoptosis (cell death), ion homeostasis, metabolic pathways and in the production and consumption of reactive oxygen species (ROS).1 All these functions are significant and can affect health, energy, vitality, and aging.

Therefore, maintaining the integrity and functionality of the mitochondria is essential for health and age prevention. Research has shown that nutritional strategies, including specific diets, nutrients, and antioxidants, can play an important role in boosting mitochondrial health and may also reduce the aging process. This review will examine the unique functions of the mitochondria and the research behind specific diet types and supplements that can help boost mitochondrial health, mitigate dysfunction, and help protect mitochondria from damage.

The Importance & Function of Mitochondria

Mitochondria are self-autonomous organelles that are essential for generating metabolic energy in the form of ATP. This energy production occurs via the breakdown of macromolecules obtained from the diet (carbohydrates, fatty acids, and amino acids) through the process of oxidative phosphorylation along the electron transport chain, whereby macronutrients are oxidized, oxygen is reduced to water, and adenosine diphosphate (ADP) is phosphorylated to ATP.2

A large amount of ATP must be produced by the mitochondria every second of every day because ATP cannot be stored. At any given time, an estimated 250 grams of ATP are available in the cells.3 In fact, 25 percent of the cell volume can be taken up by mitochondria. These organelles can therefore be found in abundance in cells that require substantial energy, such as in the skeletal and heart muscle and brain tissue.3 A single cell may contain from several hundred to thousands of mitochondria, depending on its location.

To perform their functions, mitochondria require proteins for processes that are encoded mostly by nuclear genes (nDNA) and are transported into the mitochondria for use. However, mitochondria also contain their own genome, mitochondrial DNA (mtDNA), and produce their own proteins required for the mitochondrial electron transport chain.4

To maintain functional mitochondria, the processes of fission and fusion are used when cells experience metabolic or environmental stresses.5 Fusion helps mitigate stress by mixing the contents of partially damaged mitochondria as a form of complementation. Fission is needed to create new mitochondria, but it also contributes to quality control by enabling the removal of damaged mitochondria and can facilitate apoptosis (cell death) during high levels of cellular stress.5

Mitochondrial Health, Oxidation & Aging

Research has suggested that mitochondrial function declines with age and can diminish overall health via lowered oxidative capacity, reduced oxidative phosphorylation, decreased ATP production, increased reactive oxygen species (ROS) generation, and reduced antioxidant defense.

The free radical theory of aging suggests that 1 to 3 percent of oxygen consumed by mitochondrial ATP production generates ROS, which is oxidative stress; therefore, the more energy expended as a function of time or because of a high metabolic rate, the greater the chance of oxidative damage to cells and tissues.6 Although ROS are known to be deleterious, ROS can also work as a cellular signal to trigger functions that are critical for the normal physiological function of the cell.6

Additionally, mtDNA integrity and functionality may be compromised by mutation because of oxidative damage induced by ROS, but also by environmental factors. In fact, mtDNA have a higher rate of mutation (15 times higher) and less efficient repair machinery than nDNA.7

These mutations are deleterious for high-energy-demand tissues such as muscles, the heart, the brain, and the endocrine system. mtDNA mutations may also lead to limited functioning of the electron transport chain and thus less energy production. Mutations in mtDNA that alter the expression of oxidative phosphorylation complexes can lead to mitochondrial dysfunction and accelerated ROS generation.7

Mitochondrial biogenesis also declines with age because of alterations in mitochondrial mitophagy, an autophagy process that removes dysfunctional mitochondria. Age-dependent abnormalities in mitochondrial quality control further weaken and impair mitochondrial function. In aged tissues, enhanced mitochondria-mediated apoptosis contributes to an increase in the percentage of apoptotic cells.

However, studies have shown that restricting calories, modifying diet macronutrients, and increasing dietary antioxidants can help lower mitochondria ROS production and reduce mitochondrial dysfunction and mitochondrial aging.

Nutritional Strategies That Influence Mitochondrial Health

Calorie Restriction

Calorie-restriction diets have long been associated with increased life span in animal models.2 It is suggested that this increase in life span is the result of different mechanisms, which may include the induction of mitochondrial biogenesis and the reduction of ROS. Calorie-restriction diets have been suggested to decrease mitochondrial electron flow, thereby reducing the amount of ROS and attenuating damage.

In one study using both in vivo and in vitro analyses, calorie restriction was shown to reduce oxidative stress while also stimulating the proliferation of mitochondria through the peroxisome proliferation-activated receptor coactivator-1a (PGC-1a) signaling pathway.8

Additionally, mitochondria under calorie restriction showed less oxygen consumption, reduced membrane potential, and generation of less ROS than controls, while maintaining their ATP production. This reduction in oxidative stress helped to maintain balance in the electron transport chain. In this model, calorie restriction was shown to induce a PGC-1a dependent increase in mitochondria, reducing oxidative stress and attenuating age-dependent oxidative damage.8 It’s suggested that calorie restriction activates diverse regulatory pathways that greatly enhance stress resistance via the SIRT1 pathway and markedly improve bioenergetics through the activation of the PGC-1α pathway.8

SIRT1 is a member of the family of sirtuins, signaling proteins that help regulate stress and metabolism and may promote longevity via calorie-restriction regimes. It’s been suggested that SIRT1 may mediate significant changes in tissues and endocrine systems through AMPK-targeted gene regulation, whereby the sensing of low-calorie restriction diets triggers physiological changes that benefit health and hence longevity.9

Ketogenic Diets & Mitohormesis

Glucose restriction can lead to increased mitochondrial activity, which can cause a transient higher induction of ROS production. This has been demonstrated to increase life span by inducing the mitohormesis adaptive response against ROS.10 Mitohormesis is the induction of a reduced amount of mitochondrial stress that leads to an incremental improvement in health and viability within a cell, tissue, or organism.

High ROS content induced by dietary restrictions signals for mitochondrial adaptions by initiating defense mechanisms to subsequently reduce ROS levels.11 Signaling events may influence downstream pathways of insulin/IGF-1 receptors and promote stress resistance and autophagy in mitochondria. Therefore, less mtDNA damage and mutation occur.11

In a series of experiments on the roundworm Caenorhabditis elegans, glucose metabolism was inhibited by knockdown of the insulin receptor, insulin-like growth factor 1 (IGF-1) receptor, and insulin receptor substrate 1 (IRS-1).12 Inhibition of glucose metabolism increased mitochondrial respiration associated with ROS-dependent increases in life span, stress resistance, and antioxidant enzyme activity.

A study on hippocampal mitochondrial function in rats supports the induction of mitohormesis by a ketogenic diet.13 After day one, hydrogen peroxide (H2O2) production by isolated mitochondria was increased. After day three, mtROS were also increased, further indicating an increase in oxidative stress. After one week, upregulation of antioxidant signaling occurred, which persisted through the remainder of the study. By the third week, mitochondrial H2O2 production decreased to below baseline. The ketogenic diet resulted in an initial increase in oxidative stress followed by a decrease.

Further to this, in another study on rats fed a ketogenic diet for 22 days, mitochondrial density in the hippocampus increased.14 Similarly, mitochondrial content (mtDNA copy number) increased in skeletal muscle of mice fed a ketogenic diet for 10 months.15

In young men, after 3 days of a low-carbohydrate, high-fat diet, fat oxidation significantly increased, and 49 percent of the variance was explained by higher muscle mtDNA content.16 Despite this, the content of mtDNA didn’t change significantly, but this was expected given the brief duration of the diet.

Ketogenic and caloric-restriction diets may therefore initiate mitohormetic signalling through a variety of pathways, increasing catecholamines or adiponectin, decreasing insulin or glycogen, or increasing b-oxidation, leading to an increase in mtROS.10 This could lead to further signalling involving AMPK, SIRT1, PGC-1a, among others, leading to transcription of genes related to oxidative capacity, mitochondrial uncoupling, and antioxidant defense.10 These adaptations could contribute to resistance against oxidative stress, as well as the promotion of mitochondrial biogenesis.

Supplement Strategies That Influence Mitochondrial Health

Beta-Hydroxybutyric Acid – GoBHB

Using a BHB (3-hydroxybutryric acid), a pure exogenous ketone salt, can help accelerate ketosis by providing the benefits of elevated blood ketone levels and enhance keto-adaptation. GoBHB, by NNB Nutrition, is a naturally occurring, clean-burning fuel substrate that can be used by the brain and muscles to support improved endurance, performance, and recovery, but it may also help to boost mitochondrial health.

Ketones can influence antioxidant defense. Furthermore, ketone metabolism is highly relevant to mitochondrial adaptation because the ketogenic and ketolytic enzymes needed to support nutritional ketosis are in mitochondria.17BHB contributes to protection against oxidative stress by decreasing production of mtROS by increasing expression or protein content of antioxidant enzymes through histone deacetylase inhibition, and by directly scavenging the hydroxyl radical. Upregulation of antioxidant enzymes via inhibition induces SOD, catalase, and other antioxidants and is most likely mediated via transcription factor FOXO3.17

In rats, injection of BHB increased activities of SOD and catalase and prevented the increase in lipid peroxidation and decreases in SOD, catalase, and GSH induced by paraquat injection, all of which were observed in kidney homogenate.18 In another study demonstrating ketones’ effects on mitochondrial ROS production, treatment of rat hippocampal slices with BHB and the other ketone ACA prevented the increase in mtROS and mitigated the decrease in ATP production.19 It’s also been shown that ketones can help promote repair of complexes in the electron transport chain, helping influence mitochondrial respiration.

BHB may also work as a bioenergetic signal for mitohormesis. In mice fed ketogenic diets and fasting diets, increased blood BHB concentrations resulted in increased expression of mitochondrial and antioxidant genes related to induction of mitohormesis, including upregulation of peroxisome proliferator-activated receptor a (PPARa) signaling, oxidative phosphorylation, and fatty acid metabolism.20, 21

Co-Enzyme Q10

Co-enzyme Q10 (CoQ10) is produced in the mitochondrial matrix membrane and is a critical part of the electron transport chain (ETC), and it thus plays a role in mitochondrial bioenergetics.17 CoQ10 accepts electrons from different donors, including Complex I, Complex II, the oxidation of fatty acids, and branched-chain amino acids via flavin-linked dehydrogenases and electron transfer factor Q oxidoreductase (ETF-QO) to Complex III.22 It is therefore a structural part of CI and CIII and associated with respiratory supercomplexes.

CoQ10 is also an obligatory factor in proton transport by uncoupling proteins (UCPs) with regulation of mitochondrial activity.23 CoQ10 works as an intramitochondrial antioxidant providing protection against ROS, maintaining the reduced state of vitamin E and vitamin C, and by regulating apoptosis by preventing lipid peroxidation of the membrane phospholipids.23 Evidence suggests that part of the antioxidant effects of CoQ10 is by enhancing the enzymatic activity of antioxidant proteins superoxide dismutase (SOD) and glutathione peroxidase (GPx).23

In one study of mitochondrial respiratory chain disorders, CoQ10 supplementation helped restore electron flow in MRC and/or increased mitochondrial antioxidant capacity.24 CoQ10 deficiency can also manifest as mitochondrial disorders. CoQ10 supplementation can improve some symptoms for CoQ10 synthesis deficiency.25

In a study in 12 patients with oxidative phosphorylation defects, ATP synthesis was evaluated after receiving a mixture of CoQ10, L-carnitine, vitamin B complex, vitamin C, and vitamin K1 for 12 months.26 ATP synthetic capacity in lymphocytes was significantly increased after treatment, although none of the patients improved clinically. Exposure of control lymphocytes in vitro to the various agents showed that only CoQ10 increased ATP synthesis in a dose-dependent manner.

CoQ10 supplementation may therefore help increase ATP production and work as an effective antioxidant against mtROS.


Creatine is a well-researched supplement used mostly for increasing muscle strength, power, and lean mass, ultimately by providing more energy. Creatine is a guanidino compound produced endogenously by the liver, kidney, and pancreas via the biosynthesis of arginine, glycine, and methionine.

The phosphagen energy system is the metabolic system that produces ATP most rapidly, as compared to glycolysis or the aerobic system.27 Inside the cell, creatine phosphokinase catalyzes a reversible reaction between the γ-phosphate group of ATP to the guanidino group of creatine, resulting in ADP and phosphocreatine. Cellular stores of phosphocreatine are essential for replenishing ATP stores that are immediately used during high-intensity exercise.27

Creatine has been shown to provide protection for both mtDNA and nDNA against ROS-mediated damage. Using a PCR-based assay to identify the level of DNA damage, a study found that there were increased levels of protection of the DNA in creatine-treated, hydrogen peroxide-exposed mtDNA compared to control-treated, hydrogen peroxide-exposed DNA.28 The levels of protection that creatine afforded approached the levels observed in control DNA that was not exposed to ROS.

The effect of a combination therapy of creatine monohydrate, CoQ10, and lipoic acid to target cellular energy consequences of mitochondria disorders was assessed using a randomized, double-blind, placebo-controlled, crossover study design.29 The combination therapy resulted in lower resting plasma lactate as well as attenuation of a decline in strength in all patient groups. Together, these results suggest that combination therapies targeting multiple final common pathways of mitochondrial dysfunction favorably influence surrogate markers of cellular energy dysfunction.29

In a randomized crossover study, the effects of creatine monohydrate supplementation (5 grams for 14 days or 2 grams for 7 days) were evaluated in mitochondrial cytopathy patients.30 Creatine treatment resulted in significantly increased handgrip strength, dorsiflexion torque, and postexercise lactate, with no changes in the other measured variables. The study found that creatine monohydrate increased the strength of high-intensity anaerobic and aerobic type activities in patients with mitochondrial cytopathies but had no apparent effects upon lower intensity aerobic activities.30


Resveratrol is a natural antioxidant polyphenol compound that is found in many foods, including grapes, red wine, nuts, and blueberries. This compound is mostly concentrated in the skin and seeds of grapes and berries.

Resveratrol may work by increasing mitochondrial ATP production, protecting against ROS, and by working as a calorie restriction mimetic by upregulating SIRT1.31 As discussed, SIRT1 has been shown to contribute to the life span-extending effects of calorie restriction through modulation of mitochondrial function such as increasing the mitochondrial biogenesis or attenuating mitochondrial oxidative stress by an increased antioxidant defense.

Resveratrol activates SIRT1, resulting in mitochondrial biosynthesis and a higher mtDNA content.31 One mechanism by which this may occur is via the activation of the PGC-1a pathway, which is an important transcriptional activator for mitochondrial synthesis, preventing mtDNA loss.31 SIRT1 also increases mitochondrial oxidative metabolism and decreases ROS production by increasing antioxidant enzymes.

In a study in mice, resveratrol treatment was shown to significantly increase aerobic capacity, shown by an increase in running time and consumption of oxygen in muscle fibres.32 The researchers associated resveratrol’s effects with an induction of genes for oxidative phosphorylation and mitochondrial biogenesis via targeting of SIRT1 and activating PGC-1α acetylation and an increase in PGC-1α activity.

The effects of resveratrol were seen in both muscle and brown adipose tissue (BAT), and resulted in an increase in mitochondrial function, which translated into an increase in energy expenditure, improved aerobic capacity, and enhanced sensorimotor function.32 Additionally, mice on a high-fat diet were consequently protected from the development of obesity and remained insulin sensitive when they were treated with resveratrol. These observations therefore extend the function of the SIRT1-PGC-1α axis beyond control of liver gluconeogenesis to adaptive thermogenesis in the BAT and muscle function.32

Curcumin – CurcuPrime

Curcumin is the bioactive compound isolated from turmeric, which is commonly used in South Asian cooking. Curcumin has been shown to directly target specific cellular signalling pathways with strong antioxidant effects. Curcumin lacks bioavailability, which is the rate at and extent to which an active is absorbed and reaches its target for action. Curcumin is therefore poorly absorbed when consumed orally. However, CurcuPrime by NNB Nutrition is a 100 percent naturally sourced tetrahydrocurcumin (THU).

This bioactive metabolite of Curcumin and also Zingiber has been shown to have better solubility, longer half-life, and more bioactivity than regular curcumin, as well as being more effective than other metabolites of curcumin. THU has been shown to be more stable and readily absorbed in the gastrointestinal tract, overcoming low bioavailability and therefore making THU more pharmacologically active.33

In one study, the effect of THU on antioxidant status was examined in streptozotocin-nicotinamide induced diabetic rats that received 80 milligrams per kilogram of body weight of THU for 45 days.34 Results showed not only a significant reduction in blood glucose and increase in plasma insulin but also a significant increase in the activities of specific antioxidants, including superoxide dismutase (SOD), catalase (CAT), glutathione peroxides (GPx), glutathione-S-transferase (GST), vitamin C and vitamin E.34 It also caused the reduction in the formation of free radicals and protection against lipid peroxidation induced membrane damage.

Elevated ROS levels and oxidative stress are associated with mitochondrial dysfunction. CurcuPrime may act as both an antioxidant and a free radical scavenger, providing protection against oxidative damage and preventing mitochondrial dysfunction.

Dihydroberberine – GlucoVantage

Dihydroberberine (DHB) is the active metabolite of berberine. Berberine is an alkaloid extracted from the barberry shrub (Berberis vulgaris) and has traditional uses in Chinese and Ayurvedic medicine for approximately the last 2500 years. It has shown to be effective for improving blood glucose disposal, improving insulin efficiency, lipid metabolism, and body composition.35 Its effectiveness is comparable to pharmaceuticals used for the same purposes, including for the treatment of diabetes, obesity, and metabolic syndrome.

Berberine has been shown to regulate glucose and lipid metabolism, working on both adipocytes and myocytes, and within these cell types, berberine induces a variety of metabolic effects consistent with AMPK activation.

In the body, after ingestion of berberine, gut microbes reduce it to DHB, which is then converted back to berberine after absorption by the intestines. Compared with supplementing with just berberine, NNB Nutrition’s GlucoVantage DHB has 5 times more intestinal absorption, which means you would need to take 5 times the amount of berberine to get the same result as DHB.36 It’s also longer acting in the body, lasting 8 hours compared to just 4 hours with berberine.

GlucoVantage DHB’s increased bioavailability in the intestine is because of its unique structure compared to berberine, which allows for easier absorption and easier binding at the cellular level. This form of berberine is therefore more readily available to the body. It skips the rate-limiting step that regular berberine must undergo, allowing for lower doses and possibly faster effects.

When it comes to mitochondrial health, DHB may play a role in enhancing ketogenic activity, particularly when combined with ketone BHB. In a human pilot study, DHB with BHB at a 300-milligram dose was found to increase ketone activity by 2 to 3 times over exogenous ketone supplements alone.37

DHB also works on AMPK activation. Adenosine monophosphate-activated protein kinase (AMPK) is a key fuel sensor of cellular energy status, regulating cellular and whole-body homeostasis. AMPK is activated by ratios of adenosine monophosphate (AMP) to ATP and/or ADP to ATP.38

When cellular energy (ATP) levels fall, AMPK induces catabolic pathways that generate ATP, the energy needed by cells to function, while inhibiting anabolic pathways and other pathways that consume ATP.1 This energy switch can influence multiple pathways, including lipid and glucose metabolism, protein metabolism, autophagy, and mitochondrial biogenesis.39

In one study, berberine supplementation was shown to increase skeletal muscle mitochondrial biogenesis and improve mitochondrial function in a rodent model of diet-induced obesity. After diet-induced obesity, berberine supplementation was able to revert mitochondrial dysfunction by restoring ATPase and electron transport chain activities.39 Results showed that the beneficial effects of berberine on mitochondrial biogenesis and function are dependent on the presence of SIRT1, pointing to an essential role for SIRT1 in the molecular pathway mediating the effects of berberine. SIRT1 activation by BBR may lead to a secondary activation of AMPK.40 These effects were associated with significant reductions in adiposity and improvements in overall insulin sensitivity.40


L-Ergothioneine – MitoPrime

L-ergothioneine (ET) is a thiol form of the natural amino acid histidine and is considered an anti-aging, super-antioxidant compound. Thiol-based antioxidants are considered the most powerful antioxidants in nature. In the diet, ET can be found in mushrooms, black and red beans, garlic, oat bran, and organ meat. ET appears to have strong antioxidant capabilities, working to reduce oxidative stress, modulate the inflammatory response, and help protect the cells and DNA of the body from damaging effects.

In fact, cells and tissues exposed to oxidative stress have higher concentrations of ET and specific transporters for ET in the body.5 Ergothioneine transporters (ETT) move ET throughout the body via the blood, storing it in locations that are high in free radical activity. Cells lacking ETT are more susceptible to oxidative stress, resulting in increased mtDNA damage, protein oxidation, cytokine inflammatory response, and lipid peroxidation.41 Additionally, it prevents lipid peroxidation and protects both mitochondria and mtDNA.


ET has been shown to prevent free radical-induced DNA damage by eliminating ROS, reactive nitrogen species (RNS), and reactive chlorine species (RCS) in the form of two DNA-destroying acids (hypochlorous and hypobromous). Most antioxidants cannot protect against RCS.

RCS is a strong free radical that attacks mtDNA, producing mutagenic DNA lesions. These lesions can alter the DNA, resulting in wrong DNA encoding and messaging, producing the wrong proteins. ET can scavenge RCS and also protect and repair both nDNA and mtDNA.

An in vitro study showed that ET exposure of human-derived cells protects mitochondrial DNA from oxidative stress when ETT isn’t expressed.41 ET treatment effectively prevented free radical-induced DNA damage in a dose-dependent manner. When ETT was removed, ET-treated cells yielded much higher viability rates—a 40 percent increase—over those without treatment. ET can directly protect against DNA damage, intercepting damage induced by UV radiation before it could negatively affect cells. The ETT location therefore helps transport ET to defend against substances that could damage it, protecting cellular integrity

ET has also been found to have higher antioxidant capacity, particularly compared to other common antioxidants such as glutathione, CoQ10 and vitamin C. A study showed that ET was the most active scavenger of free radicals as compared to the super-antioxidant glutathione and other antioxidants.42 In another study, ET was found to eliminate all oxidants up to 3000 percent better than glutathione and to decrease lipid peroxidation 200 percent better than glutathione.43 It also has a higher half-life: 5400 percent times longer than glutathione.

Compared with CoQ10, ergothioneine was more than twice as effective when cells were exposed to a toxin and analyzed for their ability to limit lipid peroxidation. The study found ergothioneine was 270 percent better than CoQ10.44 An in vitro study showed that mushroom-derived ergothioneine outperformed vitamin C and glutathione in its scavenging ability against reactive species.45

NNB Nutrition’s MitoPrime is a premier form of L-ergothioneine. It’s extracted using a patented technology to produce a highly bioavailable L-isomer form of ergothioneine that is 100 percent pure and all natural, with GRAS status from the FDA.

Nutrition + Effective Supplements = Mitochondrial Health

Combining effective nutrition protocols such as calorie-reduced diets and ketogenic diets with effective supplements can help provide protection to mitochondria by reducing mitochondrial stress, reducing mtDNA damage and dysfunction, and thus improving mitochondrial health. NNB Nutrition provides effective, patented supplements, including CurcuPrime, GoBHB, GlucoVantage, and MitoPrime, that help boost mitochondrial health but also high-quality ingredients that can be used in combination with calorie-reduced and ketogenic diets for the ultimate mitochondrial boost.

For more information on NNB Nutrition, go to www.nnbnutrition.com.


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