Pyrroloquinoline quinone (PQQ) was only “discovered” and researched 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 especially
2. its unique ability for mitochondrial biogenesis (= new formation of mitochondria)

A) PQQ as a powerful antioxidant

In general, free radicals, so-called "reactive oxygen species" (ROS) and "reactive nitrogen species" (RNS), are produced by various metabolic processes. In low ("normal") concentrations, they modulate various physiological processes. It only becomes problematic when the ROS or RNS production is either too high and/or the antioxidant detoxification functions are too low.

Reasons for increased radical formation can be: high levels of environmental toxins and heavy metals, medication, chronic inflammation and chronic stress, etc. Too high levels of radicals pose a high risk of damage to mitochondrial DNA (mtDNA). The ring-shaped mtDNA is contained in the mitochondrial matrix and is highly susceptible to damaging reagents. In contrast to the DNA in the nucleus of every human cell, mitochondrial DNA has little protection and repair mechanisms. Mitochondria are therefore less well protected and are also exposed to far greater stress than the rest of the cell structures, as free radicals are constantly being produced as part of mitochondrial energy production.

In addition, the increase in radicals inhibits enzyme activity (especially in the case 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 mitochondrion or the cell is no longer available for ATP production. This loss of energy leads to numerous symptoms that are 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 point of origin. The very stable molecular structure of PQQ is responsible for its high "performance" in terms of antioxidant capacity in the area of ​​electron transport in the respiratory chain. It has proven to be particularly effective in neutralizing superoxide and hydroxyl radicals. According to the latest findings, PQQ is up to 5000 times more efficient than vitamin C, for example. This is because PQQ is able to generate an almost continuous redox cycle (i.e. the ability to carry out repeated oxidation and reduction reactions): PQQ can, for example, carry out 20,000 transformations (oxidations and reductions), whereas vitamin C only manages 4.

B) PQQ and mitochondrial biogenesis

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

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

If this system no longer works, the body can no longer generate sufficient energy and performance drops. On average, a healthy adult converts ADP to ATP around 3000 times a day. In kilograms, this corresponds to around 70 kg - as much as your own body weight!

Mitochondria have their own genetic makeup. Unfortunately, they do not have the same repair systems as our cell DNA. Damage to mitochondrial DNA cannot therefore be repaired in the same way. In addition, mitochondrial DNA is subject to greater influence from free radicals that arise directly in the cellular respiration process. It is logical that a human body with a large proportion of damaged mitochondria does not have good cell performance. Poor cell performance means poor organ performance, and this leads to poor overall health and even serious disorders. This could be seen as a natural process, since a 90-year-old only has around 20% of functioning mitochondria. Poor performance and illness are the inevitable result. But it is not just the low number of mitochondria that affects us as we age. Defective mitochondria are not simply "switched off"; they do not produce any energy due to "defective" respiratory chains, but instead produce a lot 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 influences were known that can 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 the function and formation of mitochondria by activating certain genes (gene expression) that ensure the development, formation and protection of mitochondria. 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 Fig. https://www.jbc.org/article/S0021-9258(20)66100-2/fulltext )In addition, PGC-1α plays a key role in the neutralization of free radicals (ROS) by regulating the expression of numerous ROS-detoxifying enzymes (including SOD2 and GPX1).

Possible therapeutic use of PQQ

The potential therapeutic use of PQQ is derived from the above properties:

neuroprotection

• PQQ has a neuroprotective effect and has a positive influence on memory functions. For example, it was shown to improve blood flow to the brain 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 (center of emotions) from 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 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 double-blind, placebo-controlled clinical study on humans conducted in Japan in 2009.  In this study of 71 people between the ages of 40 and 70, supplementing with 20 mg of PQQ per day resulted in improvements in tests of higher cognitive functions compared to the placebo group. But 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 over the age of 50 would be better off taking PQQ together with CoQ10. However, for most people under 50, it is not necessary to take CoQ10 as their bodies usually produce sufficient amounts themselves (our bodies can produce CoQ10 themselves - but PQQ cannot), unless they are taking medications such as cholesterol-lowering statins that interfere with 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

In line with the results from cerebral infarction, PQQ (so far only data from animal experiments are available / clinical trials on humans are pending) administered directly before, during and after a heart attack causes less damage. This effect seems to be better than that of metoprolol (a standard drug for protection against reperfusion damage 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) could be 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 decreasing insulin sensitivity in people with diabetes results in higher blood sugar with the same insulin secretion from the islet cells of the pancreas. If insulin sensitivity is improved, insulin can work better 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

For example, in a study of people aged 21 to 34 years, those who received PQQ experienced significant increases in antioxidant activity, anti-inflammatory effects and energy production – 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 psychological 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.

improving sleep quality

A study conducted on 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 PQQ supplementation (~20 mg per day) resulted in statistically significant decreases 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 so far, but in very small amounts. Foods rich in PPQ include kiwi, natto, parsley, green 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 about 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 cannot therefore possibly be achieved through diet.

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

mitochondrial complex

In addition to PQQ, the following micronutrients can improve and stabilize mitochondrial function:

• 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-glutathione: 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