Pyrroloquinoline quinone (PQQ) was only “discovered” and studied in more detail a few years ago. PQQ showed two very interesting properties that distinguish this substance from other vital substances:

1. its antioxidant strength, but v.a.
2. its unique ability for mitochondrial biogenesis (= new formation of mitochondria)

A) PQQ as a powerful antioxidant

Free radicals, known as reactive oxygen species (ROS) and reactive nitrogen species (RNS), are generally produced through various metabolic processes. In low ("normal") concentrations, they modulate various physiological processes. Problems only arise when ROS or RNS production is either too high and/or the antioxidant detoxification functions are too low.

Reasons for increased radical formation can include: high exposure to environmental toxins and heavy metals, medication use, chronic inflammation, and chronic stress, among others. Excessive exposure to radicals poses a particularly high risk of damage to mitochondrial DNA (mtDNA). The circular mtDNA is contained within the mitochondrial matrix and is highly susceptible to damaging reagents. Unlike the DNA in the nucleus of every human cell, mitochondrial DNA has little protection and repair mechanisms. Mitochondria are therefore less well protected and, moreover, exposed to far greater stress than the rest of the cellular structures, as free radicals are constantly produced during mitochondrial energy production.

In addition, the increase in radicals inhibits enzyme activity (especially in the case of
of the respiratory chain) and increases the permeability of the inner mitochondrial membrane. Increased permeability of the inner membrane, in turn, promotes the release of cytochrome c into the cytosol, a cytotoxic substance that ultimately causes cell death (apoptosis). As a result, the mitochondria or cell are no longer available for ATP production. This energy loss leads to numerous symptoms, often accompanied by physical exhaustion, fatigue, and listlessness.

Fig.: Structure of mitochondria

PQQ is located directly in the mitochondria and can therefore neutralize free radicals directly at the site of their formation. The very stable molecular structure of PQQ determines its high "performance" in terms of its antioxidant capacity in the area of ​​electron transport in the respiratory chain. It has proven particularly effective in neutralizing superoxide and hydroxyl radicals. According to the latest findings, PQQ is up to 5000 times more effective than, for example, vitamin C. This is due to PQQ's ability to maintain a nearly continuous redox cycle (d.h. the ability to carry out repeated oxidation and reduction reactions): PQQ, for example, can carry out 20,000 transformations (oxidations and reductions), whereas vitamin C can only carry out 4.

B) PQQ and mitochondrial biogenesis

Mitochondria are the energy powerhouses of all living organisms. They are approximately 1-5 µm-sized cell organelles that are found in almost every cell in the body in varying densities, depending on energy needs. While individual heart, liver, and brain cells each contain between 2,000 and 10,000 mitochondria, erythrocytes are the only cells that do not.

In the mitochondria, energy is produced via so-called "respiratory chains," each consisting of four large protein complexes (I-IV) and another complex (V), ATP synthase. With the help of electrons and protons from the upstream citric acid cycle, ATP synthase generates ADP to ATP while consuming oxygen.ATP (adenosine triphosphate) acts as an energy carrier in cells and is essential for the functioning of all vital processes in the body.

If this system no longer functions, the body can no longer generate sufficient energy, and performance declines. On average, a healthy adult converts ADP to ATP approximately 3,000 times per day. In kilograms, this corresponds to approximately 70 kg—equivalent to one's own body weight!

Mitochondria have their own genetic makeup. Unfortunately, they don't have the same repair systems as our cellular DNA. Damage to mitochondrial DNA therefore cannot be repaired equally well. In addition, mitochondrial DNA is more susceptible to free radicals, which are generated directly during cellular respiration. Logically, a human body with a high proportion of damaged mitochondria will not perform well in cells. Poor cell function translates into poor organ function, and this can lead to poor overall health and even severe disorders. One could view this as a natural process, given that a 90-year-old only has about 20% of their mitochondria functioning. Reduced performance and disease are the inevitable consequences. But it's not just the reduced number of mitochondria that affects us as we age. Defective mitochondria aren't simply "switched off"; instead, they produce no energy due to defective respiratory chains, but instead produce a great deal of oxidative stress. The resulting free radicals in turn have a negative effect on still “healthy” mitochondria (cf. https://pubmed.ncbi.nlm.nih.gov/20552048/ )

PQQ now has the unique ability to stimulate the formation of new mitochondria in aging cellsBefore the discovery of PQQ, only two factors were known to stimulate the formation of new mitochondria:

• Extensive, aerobic endurance training
• Calorie reduction or use of calorie restriction mimetics such as resveratrol

Pyrroloquinoline quinone (PQQ) promotes mitochondrial function and formation by activating specific genes (gene expression) that ensure mitochondrial development, regeneration, and protection. Important mitochondrial repair mechanisms are also activated. PQQ not only generates new mitochondria, but the mitochondria are also larger and have a higher mass.

PQQ increases the expression of PGC-1α (Peroxisome Proliferator-Activated Receptor Gamma Coactivator-1Alpha), one of the most important factors for the activation of genes that stimulate mitochondrial growth (see. https://www.jbc.org/article/S0021-9258(20)66100-2/full text ). In addition, PGC-1α is involved in regulating the expression of numerous ROS-detoxifying enzymes (u.a. SOD2 and GPX1) are significantly involved in the neutralization of free radicals (ROS).

Possible therapeutic use of PQQ

From the o.gThe potential therapeutic use of PQQ is derived from these properties:

Neuroprotection

• PQQ has a neuroprotective effect and a positive influence on memory functions. For example, it has been shown to improve cerebral blood flow and oxygen utilization in the prefrontal cortex, the area of ​​active thinking (see Nakano M, Murayama Y, Hu L, et al. Effects of Antioxidant Supplements on Cerebral Blood Flow and Oxygen Metabolism in the Prefrontal Cortex. Adv Exp Med Biol. 2016;923:215-222).
• PQQ stimulates the “nerve growth factor”

• PQQ is a powerful antioxidant (“radical scavenger”), which could be one reason why PQQ protects against stroke.

• PQQ protects against oxidation processes in the brain and thus potentially also against Parkinson's disease
• PQQ has a neuroprotective effect against 6-hydroxydopamine-induced hypoxia (oxygen deficiency) and ischemia
• PQQ can reduce the size of damaged brain areas in a stroke
• PQQ counteracts the formation of amyloid fibrils, which are the main factors in the development of Alzheimer's disease.
• PQQ can protect against the damaging effects of mercury in the brain.
• PQQ protects neurons in the hippocampus region (the center of emotions) from the damaging effects of glutamate. Fewer neurons were damaged. PQQ activates "antioxidant genes."

Sources:

https://pubmed.ncbi.nlm.nih.gov/22843070/

https://pubmed.ncbi.nlm.nih.gov/12383230/

Excursus: Combination of PQQ with coenzyme Q10 is useful in relation to brain function in people over 50

In terms of improving brain function, even better results were observed when PQQ was combined with coenzyme Q10. This synergistic effect was further demonstrated in a 2009 double-blind, placebo-controlled human study conducted in Japan. In this study of 71 people between the ages of 40 and 70, supplementing with 20 mg of PQQ per day led to improvements in tests of higher cognitive function compared to the placebo group. However, the results were even more impressive in the group that received 20 mg of PQQ along with 300 mg of coenzyme Q10.

It therefore seems that people older than 50 should take PQQ together with CoQ10. However, for most people under 50, it is not necessary to take CoQ10, as their bodies i.d.R. produce sufficient amounts ourselves (our body can produce CoQ10 itself – but not PQQ), unless we are taking medications such as cholesterol-lowering statins, which impair CoQ10 production.

Source: Itoh Y, Hine K, Miura H, et al. Effect of the antioxidant supplement pyrroloquinoline quinone disodium salt (BioPQQ™) on cognitive functions. Adv Exp Med Biol 2016;876:319-325.

Heart attack and protection of heart cells

Consistent with the results obtained in cerebral infarction, PQQ (currently only animal data are available; clinical trials in humans are pending) causes less damage when administered directly before, during, and after a heart attack. This effect appears to be better than that of metoprolol (a standard medication for protecting against reperfusion injury during and after a heart attack). Source: https://pubmed.ncbi.nlm.nih.gov/16891289/

PQQ was also able to protect animal heart cells from oxidative stress and mitochondrial dysfunction. The increased formation of free radicals triggered by hydrogen peroxide (H2O2) was reduced in the heart muscle cells by PQQ. Source: https://www.sciencedirect.com/science/article/abs/pii/S0006291X07017123

Improving insulin sensitivity in type 2 diabetes

PQQ can improve insulin sensitivity in diabetes. The decreased insulin sensitivity in diabetics results in higher blood sugar levels with the same insulin secretion from the pancreatic islet cells. If insulin sensitivity is improved, insulin can become more effective again. Source: https://www.sciencedirect.com/science/article/abs/pii/S0006291X12020098

Protection against radiation damage

PQQ appears to protect against radioactive gamma rays.
Sources:
https://onlinelibrary.wiley.com/doi/abs/10.1002/jobm.201100650
https://pubmed.ncbi.nlm.nih.gov/22272111/

Reduction of chronic inflammation

In a study with people between 21 and 34 years z.B. significant increases in antioxidant activity, anti-inflammatory effects, and energy production were observed in those who received PQQ—even after just one dose.

Source: Harris CB, Chowanadisai W, Mishchuk DO, et al. Dietary pyrroloquinoline quinone (PQQ) age indicators of inflammation and mitochondrial-related metabolism in human subjects. J Nutr Biochem. 2013 Dec;24(12):2076-84.

Improvement of mental mood

Seventeen healthy middle-aged and older subjects were given 20 mg of PQQ or a placebo daily for eight weeks. PQQ was shown to significantly improve all six measures of the Profile of Mood States (POMS)—vitality, fatigue, anxious tension, depression, anger-hostility, and confusion.

Source: Koikeda T, Nakano M, Masuda K. Pyrroloquinoline quinone disodium salt improves higher brain function. Med. Consult. New Remedies. 2011;48:519–527.

Improve sleep quality

A study conducted with middle-aged and older subjects also found improvements in sleepiness upon awakening, sleep onset and maintenance, and sleep duration.

Source: Nakano M, Yamamoto T, Okumura H, Tsuda A, Kowatari Y. Effects of oral supplementation with pyrroloquinoline quinone on stress, fatigue, and sleep. Funct Foods Health Dis 2012;2:307–324.

Lowering LDL cholesterol

Six weeks of supplementation with PQQ (~20 mg per day) resulted in a statistically significant decrease in total cholesterol (reduction from an average of 247 to 216 mg/dl) and LDL cholesterol (reduction from an average of 156 to 132 mg/dl) in subjects with baseline LDL cholesterol levels above 140 mg/dl.

Source: Nakano M, Kawasaki Y, Suzuki N, Takara T. Effects of Pyrroloquinoline Quinone Disodium Salt Intake on the Serum Cholesterol Levels of Healthy Japanese Adults. J Nutr Sci Vitaminol. 2015;61(3):233-40.

PQQ in food

PQQ has been found in all plant foods analyzed to date, albeit in very small amounts. Foods rich in PQQ include kiwi, natto, parsley, green bell pepper, papaya, and tofu. However, 100 kg of kiwi contains only 2.7 mg of PQQ, while 100 kg of natto contains 6.1 mg; green tea contains approximately 2-3 mcg per 118 ml (cf. Kumazawa T, Sato K, Seno H, et al. Levels of pyrroloquinoline quinone in various foods. Biochem J 1995;307:331-333 and https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1136652/pdf/biochemj00065-0028.pdf).

The recommended intake of 20 mg derived from studies is therefore impossible to achieve through diet.

Since neither humans nor the bacteria that populate the human gut have the ability to synthesize PQQ, scientists classify PQQ as an essential micronutrient. There is discussion about classifying PQQ as a B vitamin (see [1]). https://www.nature.com/articles/422832a )

Mitochondrial complex

The following micronutrients can improve and stabilize mitochondrial function in addition to PQQ:

• PQQ: Increase in the number of mitochondria via gene expression (biogenesis), protection of mitochondria, enlargement of mitochondria
• Coenzyme Q10: Important enzyme of the respiratory chain
• NADH: Proton donor for the respiratory chain
• L-Glutathion: Enzymatic antioxidant protection of mitochondria
• Alpha-lipoic acid: Enzymatic antioxidant protection of mitochondria
• Trans-Resveratrol: Biogenesis and protection of mitochondria
• Cordyceps sinensis: Increases the values ​​of the SOD
• selenium: Important trace element of glutathione peroxidase, which neutralizes peroxides and hydrogen peroxide
• Phospholipids, especially phosphatidylserine: Important for the double membranes that contain the respiratory chain enzymes.
• Acetyl-L-carnitine: Necessary for the transport of free fatty acids into the mitochondria
• Antioxidant complex Cell protection of the respiratory chain