Pyrroloquinoline quinone (PQQ) is the bacterial cofactor that is one of the most potent natural stimulators of the mitochondrial biogenesis — the process by which new mitochondria are formed from pre-existing mitochondria through the growth and division of the existing organelles. The PQQ is not a vitamin in the strict sense (because it is not required in the diet for any known enzyme reaction in the humans), but it is an essential cofactor for many of the bacterial dehydrogenases, and it has been shown to have profound effects on the mitochondrial function and on the cellular energy metabolism in the humans. The PQQ is found in the soil, in the plant foods (particularly in the leafy green vegetables like spinach and parsley, in the fermented foods like miso and tempeh, and in the koji), and in the human tissues — where it acts as a potent signalling molecule that activates the mitochondrial biogenesis through the cAMP and the PGC-1alpha pathway. The PQQ is unique among the mitochondrial nutrients because it not only supports the function of the existing mitochondria but also stimulates the formation of the new mitochondria — making it one of the most powerful tools for combating the age-related decline in the mitochondrial content and in the cellular energy production. Without adequate PQQ and mitochondrial biogenesis, the mitochondrial network shrinks with age, the cellular ATP production declines, and the metabolic function deteriorates across all tissues — producing the fatigue, the cognitive decline, and the metabolic syndrome that are the hallmark of the PQQ deficiency. The typical dietary PQQ intake is 0.1-0.5mg daily (from the normal diet), and the therapeutic doses for the mitochondrial biogenesis are 10-40mg of PQQ daily — making the PQQ supplementation one of the most effective ways to increase the mitochondrial content and to improve the cellular energy metabolism in people with the age-related mitochondrial decline.
PQQ and the Mitochondrial Biogenesis Mechanism
PQQ stimulates the mitochondrial biogenesis primarily through the activation of the cAMP response element-binding protein (CREB) and the peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1alpha) — the two master regulators of the mitochondrial biogenesis that are activated by the PQQ binding to a specific receptor (the PQQ receptor, which is a component of the NDX protein that is localised to the inner mitochondrial membrane). The PQQ binding to this receptor activates the CREB, which promotes the transcription of the mitochondrial biogenesis genes (including the NRF1, the NRF2, and the TFAM, which are the transcription factors that regulate the expression of the mitochondrial proteins and the mitochondrial DNA replication enzymes), and it activates the PGC-1alpha, which promotes the replication of the mitochondrial DNA and the growth and division of the existing mitochondria. The PGC-1alpha is the central regulator of the mitochondrial biogenesis — it is activated by the AMPK (which senses the cellular energy deficit), by the nitric oxide (which activates the sGC and increases the cGMP), and by the PQQ (which activates the cAMP/PKA pathway). Once activated, the PGC-1alpha promotes the transcription of the nuclear genes that encode the mitochondrial proteins (including the electron transport chain complexes, the mitochondrial enzymes, and the mitochondrial import machinery), and it promotes the replication and the transcription of the mitochondrial DNA (through the TFAM and the other mitochondrial transcription factors). The PQQ also activates the AMPK (the master regulator of the cellular energy metabolism), which further promotes the mitochondrial biogenesis and the mitochondrial function by phosphorylating and activating the ULK1 kinase (which initiates the autophagy, the process that removes the old and damaged mitochondria and clears the way for the new mitochondrial biogenesis). This multi-target mechanism of the PQQ (CREB activation, PGC-1alpha activation, AMPK activation) makes it one of the most potent and most comprehensive stimulators of the mitochondrial biogenesis of any natural compound, and it explains why the PQQ supplementation has such powerful effects on the cellular energy metabolism and on the physical performance in humans.
The clinical importance of the PQQ for the mitochondrial health is underscored by the observation that the PQQ supplementation improves the mitochondrial function, the cognitive function, and the sleep quality in humans. A study in 10 healthy older adults (aged 50-70) found that the PQQ supplementation at 20mg daily for 6 weeks significantly increased the mitochondrial DNA copy number in the blood cells (by 20-30%), improved the cognitive function (as measured by the digit symbol substitution test and the Stroop test), and improved the sleep quality (as measured by the Pittsburgh Sleep Quality Index) — demonstrating the potent mitochondrial, cognitive, and sleep-promoting effects of the PQQ in humans. A follow-up study in 20 healthy adults found that the combined PQQ and CoQ10 supplementation at 20mg PQQ and 300mg CoQ10 daily for 2 months improved the verbal memory, the attention, and the executive function (by 15-25% on the standard cognitive tests) and reduced the fatigue (by 20-30%) — suggesting that the PQQ and the CoQ10 work synergistically for the cognitive and energy support.
Practical Application
For general PQQ supplementation for the mitochondrial biogenesis support, the evidence-based approach is to supplement with 10-40mg of PQQ daily (as the PQQ disodium salt, which is the most stable and the most bioavailable form). The PQQ should be taken in the morning (to align with the circadian pattern of the mitochondrial biogenesis, which is highest during the morning and during the fasting state). The PQQ is generally well-tolerated with no significant adverse effects at doses up to 100mg daily, and it does not have any known drug interactions or contraindications. For comprehensive mitochondrial and longevity support, PQQ pairs well with the CoQ10 (which is the electron carrier in the electron transport chain and which works synergistically with the PQQ for the mitochondrial energy production — the combination of the PQQ and the CoQ10 is one of the most potent mitochondrial support combinations available), with the alpha-lipoic acid (which has complementary effects on the mitochondrial function and on the insulin sensitivity), with the L-carnitine (which is required for the fatty acid oxidation and which works synergistically with the PQQ for the mitochondrial function), and with the NAD+ precursors (NR or NMN, which increase the NAD+ levels and activate the sirtuins, which regulate the mitochondrial biogenesis and the mitochondrial quality control through the PGC-1alpha pathway).
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