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

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

A) PQQ as a powerful antioxidant

Generally, various metabolic processes produce free radicals, so-called "reactive oxygen species" (ROS) and "reactive nitrogen species" (RNS). At low ("normal") concentrations, they modulate various physiological processes. Problems only arise when ROS or RNS production is either too high and/or antioxidant detoxification functions are too low.

Reasons for increased free radical production can include: high exposure to environmental toxins and heavy metals, medication use, chronic inflammation, and chronic stress, etc. An excessively high free radical load poses a particularly high risk of damage to mitochondrial DNA (mtDNA). The circular mtDNA is contained in the mitochondrial matrix and is highly susceptible to damaging agents. Unlike the DNA in the nucleus of every human cell, mitochondrial DNA has few protective and repair mechanisms. Mitochondria are therefore less well protected and, moreover, exposed to a far greater strain than the rest of the cell structures, since free radicals are constantly generated during mitochondrial energy production.

Furthermore, the increase in radicals inhibits enzyme activity (especially in the case of those
(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 consequence, the mitochondrion or the cell is no longer available for ATP production. This energy loss leads to numerous symptoms, often accompanied by physical exhaustion, lethargy, and lack of motivation.

Fig.: Structure of mitochondria

PQQ is located directly in the mitochondria and can therefore neutralize free radicals directly at their source. The very stable molecular structure of PQQ accounts for its high performance in terms of antioxidant capacity within the electron transport chain of 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 efficient than, for example, vitamin C. This is because PQQ is able to maintain a virtually continuous redox cycle (d.h. the ability to perform repeated oxidation and reduction reactions): PQQ, for example, can perform 20,000 conversions (oxidations and reductions), whereas vitamin C only manages 4.

B) PQQ and mitochondrial biogenesis

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

Energy is produced in the mitochondria via so-called "respiratory chains," each consisting of four large protein complexes (I-IV) and another complex (V), the ATP synthase. Using electrons and protons from the upstream citric acid cycle, the ATP synthase generates ADP to ATP, consuming oxygen in the process.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 malfunctions, the body can no longer generate sufficient energy, leading to a decline in performance. On average, a healthy adult converts ADP to ATP approximately 3,000 times per day. In kilograms, this corresponds to roughly 70 kg – about the same as their 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 in the same way. Additionally, mitochondrial DNA is more susceptible to free radicals, which are produced directly during cellular respiration. Logically, a human body with a high proportion of damaged mitochondria will not function well. Poor cellular function means poor organ function, and this leads to poor overall health, potentially resulting in serious disorders. This could be seen as a natural process, since a 90-year-old has only about 20% functional mitochondria. Reduced performance and illness are the inevitable consequences. But it's not just the low number of mitochondria that causes problems with age. Defective mitochondria aren't simply "switched off"; rather, due to "defective" respiratory chains, they produce no energy but instead generate a significant amount of oxidative stress. The resulting free radicals in turn have a negative effect on mitochondria that are still “healthy” (see [reference]). 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 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 enhances the expression of PGC-1α (Peroxisome Proliferator-Activated Receptor Gamma Coactivator-1Alpha), one of the most important factors for activating genes that stimulate mitochondrial growth (see [reference]). https://www.jbc.org/article/S0021-9258(20)66100-2/fulltext )Furthermore, PGC-1α regulates the expression of numerous ROS-detoxifying enzymes (u.a. SOD2 and GPX1) are significantly involved in the neutralization of free radicals (ROS).

Potential therapeutic use of PQQ

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

Neuroprotection

• PQQ has neuroprotective effects 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 responsible for 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 (“free radical scavenger”), which could be one reason for the protection against stroke provided by PQQ.

• 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 (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: The combination of PQQ with coenzyme Q10 is beneficial for brain function in people over 50.

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

It therefore seems that people over 50 should ideally 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 medications such as cholesterol-lowering statins are being taken, 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 in cerebral infarction, PQQ (so far only data from animal studies 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 superior to 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 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 declining insulin sensitivity in people with diabetes results in higher blood sugar levels despite the same insulin secretion from the pancreatic islet cells. Improving insulin sensitivity allows insulin to work more effectively. 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 old 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 volunteers of middle and older age 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

In a study conducted with middle-aged and older subjects, improvements were also found in terms of sleepiness upon waking, the onset and maintenance of sleep, 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

A 6-week supplementation with PQQ (~20 mg per day) led to 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-based foods analyzed to date, albeit in very small amounts. Foods rich in PQQ include kiwifruit, natto, parsley, green bell peppers, papaya, and tofu. However, 100 kg of kiwifruit 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 (see Kumazawa T, Sato K, Seno H, et al. Levels of pyrroloquinoline quinone in various foods. Biochem J 1995;307:331–333). 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 alone.

Since neither humans nor the bacteria that inhabit 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 [reference]). https://www.nature.com/articles/422832a )

Mitochondrial complex

The following micronutrients, in addition to PQQ, 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-GlutathionEnzymatic antioxidant protection of mitochondria
• Alpha-lipoic acidEnzymatic antioxidant protection of mitochondria
• Trans-resveratrolBiogenesis and protection of mitochondria
• Cordyceps sinensisIncreases the SOD values
• selenium: Important trace element of glutathione peroxidase, which neutralizes peroxides and hydrogen peroxide
• Phospholipides, especially phosphatidylserine: Important for the double membranes, which contain the respiratory chain enzymes.
• Acetyl-L-CarnitineNecessary for the transport of free fatty acids into the mitochondria
• Antioxidant complex Cell protection of the respiratory chain