Pyrroloquinoline quinone (PQQ) is a unique redox cofactor that is found in most plant-based foods (particularly in the parsley, the green tea, the kiwi fruit, and the fermented foods) and that has been shown in multiple studies to stimulate the mitochondrial biogenesis — the process by which new mitochondria are synthesised to replace the aged and the damaged mitochondria. Unlike the other mitochondrial support nutrients (CoQ10, L-carnitine, alpha-lipoic acid, magnesium), which protect the existing mitochondrial population from damage, PQQ actively stimulates the proliferation of new mitochondria, expanding the mitochondrial population in a way that the other mitochondrial support ingredients cannot achieve. This unique mitochondrial biogenesis effect of PQQ makes it one of the most promising and most interesting nutritional interventions for the prevention of the age-related mitochondrial decline and for the support of the energy metabolism, the cognitive function, and the longevity. The total body PQQ pool is very small (estimated at 0.1-0.5mg), and the dietary intake is typically 0.1-1mg daily — but despite this low intake and this small body pool, the PQQ has been shown in multiple studies to have significant effects on the mitochondrial function and on the energy metabolism.
PQQ and the CREB Signalling Pathway
The mechanism by which PQQ stimulates the mitochondrial biogenesis involves the activation of the cAMP response element-binding protein (CREB) signalling pathway — PQQ activates the CREB by increasing the intracellular cAMP levels (through a mechanism that is not yet fully characterised) and by promoting the phosphorylation of the CREB at the serine 133 residue. The activated CREB then binds to the cAMP response element (CRE) in the promoter regions of the nuclear respiratory factor (NRF) genes and activates their transcription. The NRFs (NRF-1 and NRF-2) are the transcription factors that activate the expression of the nuclear-encoded mitochondrial genes — including the subunits of the electron transport chain complexes, the enzymes of the TCA cycle, and the proteins of the mitochondrial import machinery. By activating the CREB-NRF pathway, PQQ stimulates the synthesis of the new mitochondrial proteins and the assembly of the new mitochondria, increasing the mitochondrial population and restoring the mitochondrial energy capacity in the ageing cells.
The clinical importance of PQQ for the mitochondrial biogenesis is underscored by the observation that PQQ supplementation improves the cognitive function, reduces the fatigue, and enhances the mitochondrial energy production in older adults. A study in 71 older adults found that PQQ supplementation at 20mg daily (for 8 weeks) significantly improved the cognitive function (as measured by the trail-making test and by the digit symbol substitution test) and reduced the fatigue (as measured by the Chalder fatigue scale) compared to placebo. These findings are consistent with the hypothesis that PQQ stimulates the mitochondrial biogenesis in the brain and in the other tissues, restoring the energy metabolism and improving the cognitive and the physical function in older adults.
PQQ and the Antioxidant Defence
Beyond its mitochondrial biogenesis effect, PQQ also has direct antioxidant effects — it neutralises the reactive oxygen species (ROS) and the reactive nitrogen species (RNS) and regenerates other antioxidants. PQQ is a potent scavenger of the superoxide anion, of the hydroxyl radical, and of the peroxynitrite — and it is particularly effective at protecting the mitochondrial DNA (mtDNA) from the oxidative damage, because the mtDNA is located in the mitochondrial matrix and is therefore in close proximity to the site of the ROS generation in the electron transport chain. The protection of the mtDNA from the oxidative damage is one of the most important mechanisms of the anti-ageing effect of PQQ — the mtDNA is particularly vulnerable to the oxidative damage (because it lacks the histones and the DNA repair enzymes that protect the nuclear DNA), and the accumulation of the mtDNA mutations with age is one of the primary drivers of the mitochondrial dysfunction and of the ageing process.
Practical Application
For general PQQ supplementation, the evidence-based approach is to supplement with 10-20mg of PQQ daily (as the pyrroloquinoline quinone disodium salt form, which is the most stable and the most bioavailable form). The PQQ is often combined with the CoQ10 (as the PQQ-CoQ10 combination) for the comprehensive mitochondrial support — the CoQ10 provides the electron carrier function in the existing mitochondria, while the PQQ stimulates the synthesis of the new mitochondria. For comprehensive mitochondrial and cognitive support, PQQ pairs well with the CoQ10 (as the ubiquinol form, which is the reduced and more bioavailable form), with the L-carnitine (which is required for the fatty acid transport into the new mitochondria), with the alpha-lipoic acid (which regenerates vitamin E and which has complementary effects on the mitochondrial energy metabolism), and with the acetyl-L-carnitine (which supports the mitochondrial function in the brain and which has complementary cognitive benefits).
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