PQQ — Benefits Deep Dive

Most of the proposed benefits of PQQ trace back to one laboratory finding: in mouse liver-derived cells in culture, PQQ switched on the CREB → PGC-1α signalling that makes new mitochondria (Chowanadisai et al. 2010). Separate cell and animal studies reported effects on nerve growth factor, the NMDA receptor and amyloid fibrils. In people, the evidence is a handful of small, short trials in healthy adults, mostly run or funded by manufacturers, reporting modest changes in some cognitive test scores, one open-label sleep and fatigue study, and one exercise trial in which PGC-1α rose but aerobic performance did not change. Each article below works through one area trial by trial.

Deep-Dive Articles

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Mitochondrial Biogenesis

The headline mechanism. The Chowanadisai 2010 Journal of Biological Chemistry cell-culture study behind PQQ's proposed CREB → PGC-1α → TFAM/NRF-1/NRF-2 cascade, the PQQ-deficient-mouse findings (Stites 2006), the Hwang 2020 exercise trial in which PGC-1α rose but aerobic performance did not change, and how PQQ's proposed role differs from CoQ10 and alpha lipoic acid (more mitochondria vs. better function).

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Cognition, Memory & Attention

The four small placebo-controlled trials in healthy Japanese adults — Itoh 2016 (Stroop test), Nakano 2016 (prefrontal blood flow), Shiojima 2022 and Tamakoshi 2023 (computerized test batteries) — what changed, what did not, who funded them, and three often-cited trials that could not be traced in PubMed or Crossref.

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Sleep, Mood & Mental Fatigue

The open-label Nakano 2012 study of 17 adults on 20 mg/day for 8 weeks, with no placebo group; the serotonin/melatonin and cortisol hypotheses, which have not been tested in people; and what has and has not been studied in chronic fatigue, brain fog and post-viral fatigue.

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NGF Synthesis & Neuroprotection

In cultured mouse astroglial cells, PQQ stimulated nerve growth factor synthesis (Murase 1993). The test-tube amyloid findings, PQQ's action at the NMDA receptor's redox site in cultured neurons, the animal Alzheimer's and stroke models, and lion's mane as a separate line of research — with no human trial in neurological disease.

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Table of Contents

  1. Deep-Dive Articles
  2. One Proposed Mechanism, Several Lines of Research
  3. Research Papers: Mitochondrial Biogenesis
  4. Research Papers: Cognition
  5. Research Papers: Sleep & Mood
  6. Research Papers: NGF Synthesis & Neuroprotection
  7. Research Papers: Cross-Cutting (Forms, Safety, Mechanism)
  8. External Authoritative Resources
  9. Connections
  10. Featured Videos

One Proposed Mechanism, Several Lines of Research

Many of the effects claimed for PQQ are traced back to a single proposed mechanism: activation of the CREB → PGC-1α → TFAM/NRF-1/NRF-2 cascade that drives mitochondrial biogenesis. That cascade was shown in mouse liver-derived cells in culture (Chowanadisai et al. 2010), and mice fed no PQQ had 20-30% fewer liver mitochondria than PQQ-fed mice (Stites et al. 2006). Whether oral PQQ raises mitochondrial content in human tissues has not been shown. The proposed branches, and the evidence behind each:

  1. Brain function — small 12-week trials in healthy Japanese adults (Itoh 2016, Nakano 2016, Shiojima 2022, Tamakoshi 2023) reported changes in some cognitive test scores, often in subgroups; none measured brain mitochondria. See the Cognition deep-dive.
  2. Sleep and fatigue — one open-label study of 17 adults without a placebo group (Nakano 2012) reported better mood, sleep and fatigue scores; proposed effects on sleep-regulating brain areas have not been tested. See the Sleep & Mood deep-dive.
  3. Glial cells and neurons — PQQ stimulated NGF synthesis in cultured mouse astroglial cells (Murase 1993), reduced amyloid fibril formation in the test tube (Kim 2010) and acted at the NMDA receptor's redox site in cultured neurons (Aizenman 1992). See the NGF Synthesis deep-dive.
  4. Muscle, liver, heart and reproduction — the cell work used liver-derived cells; in one trial in 23 untrained men, PGC-1α rose more with PQQ while aerobic performance did not differ (Hwang 2020); rat heart-attack and mouse reproduction studies are animal findings. See the Mitochondrial Biogenesis deep-dive.

The proposed role differs from those of CoQ10 (an electron carrier inside the existing electron transport chain), alpha lipoic acid (a cofactor of mitochondrial dehydrogenase enzymes) and methylene blue (an alternative electron carrier). PQQ is often sold together with CoQ10 on this "number plus function" reasoning, but no trial cited here has tested whether the combination does more than either compound alone.

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Research Papers: Mitochondrial Biogenesis

  1. Stites T, Storms D, Bauerly K, et al. (2006). Pyrroloquinoline quinone modulates mitochondrial quantity and function in mice. Journal of Nutrition 136:390-6 — PubMed PMID: 16424117
  2. Chowanadisai W, Bauerly KA, Tchaparian E, Wong A, Cortopassi GA, Rucker RB (2010). Pyrroloquinoline quinone stimulates mitochondrial biogenesis through cAMP response element-binding protein phosphorylation and increased PGC-1α expression. Journal of Biological Chemistry 285:142-52 — PubMed PMID: 19861415
  3. Bauerly K, Harris C, Chowanadisai W, et al. (2011). Altering pyrroloquinoline quinone nutritional status modulates mitochondrial, lipid, and energy metabolism in rats. PLoS One 6:e21779 — PubMed PMID: 21814553
  4. Hwang PS, Machek SB, Cardaci TD, Wilburn DT, Kim CS, Suezaki ES, Willoughby DS (2020). Effects of pyrroloquinoline quinone (PQQ) supplementation on aerobic exercise performance and indices of mitochondrial biogenesis in untrained men. Journal of the American College of Nutrition 39:547-56 — PubMed PMID: 31860387
  5. PGC-1α as a regulator of mitochondrial biogenesis — PubMed: PGC-1α master regulator
  6. TFAM and mitochondrial transcription factor A function — PubMed: TFAM biogenesis
  7. NRF-1 and NRF-2 nuclear respiratory factors — PubMed: NRF-1 NRF-2
  8. PQQ and exercise signalling (search) — PubMed: PQQ exercise
  9. Mitochondrial density in aging tissues — PubMed: mitochondrial density aging
  10. PQQ, caloric restriction and sirtuins (search) — PubMed: PQQ caloric restriction
  11. PQQ and skeletal muscle mitochondrial content (search) — PubMed: PQQ skeletal muscle mitochondria

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Research Papers: Cognition

  1. Itoh Y, Hine K, Miura H, Uetake T, Nakano M, Takemura N, Sakatani K (2016). Effect of the antioxidant supplement pyrroloquinoline quinone disodium salt (BioPQQ™) on cognitive functions. Advances in Experimental Medicine and Biology 876:319-25 — PubMed PMID: 26782228
  2. Nakano M, Murayama Y, Hu L, Ikemoto K, Uetake T, Sakatani K (2016). Effects of antioxidant supplements (BioPQQ™) on cerebral blood flow and oxygen metabolism in the prefrontal cortex. Advances in Experimental Medicine and Biology 923:215-22 — PubMed PMID: 27526146
  3. Shiojima Y, Takahashi M, Takahashi R, Moriyama H, Bagchi D, Bagchi M, Akanuma M (2022). Effect of dietary pyrroloquinoline quinone disodium salt on cognitive function in healthy volunteers: a randomized, double-blind, placebo-controlled, parallel-group study. Journal of the American Nutrition Association 41:796-809 (erratum: 41:855) — PubMed PMID: 34415830
  4. Tamakoshi M, Suzuki T, Nishihara E, Nakamura S, Ikemoto K (2023). Pyrroloquinoline quinone disodium salt improves brain function in both younger and older adults. Food & Function 14:2496-501 — PubMed PMID: 36807425
  5. PQQ and cortical mitochondrial density (search) — PubMed: PQQ cortical mitochondrial density
  6. CoQ10 cognition meta-analyses (search) — PubMed: CoQ10 cognition meta-analysis
  7. Aerobic exercise and cognition in older adults (search) — PubMed: exercise and cognition
  8. d-ROMs test and oxidative stress in cognitive aging (search) — PubMed: d-ROMs cognitive aging

Three trials often cited for PQQ and cognition — a 2009 Japanese trade-journal report of a 24-week trial in 71 adults, a 2018 "Korean trial" in 67 older adults, and a 2021 PQQ + CoQ10 trial attributed to Kim and colleagues — could not be found in PubMed or Crossref and are not listed.

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Research Papers: Sleep & Mood

  1. Nakano M, Yamamoto T, Okamura H, Tsuda A, Kowatari Y (2012). Effects of oral supplementation with pyrroloquinoline quinone on stress, fatigue, and sleep. Functional Foods in Health and Disease 2:307 (open-label, 17 people; not indexed in PubMed) — doi:10.31989/ffhd.v2i8.81
  2. PQQ and HPA-axis modulation (search) — PubMed: PQQ HPA axis cortisol
  3. PQQ and the serotonin / melatonin pathway (search) — PubMed: PQQ serotonin melatonin
  4. PQQ in chronic fatigue and post-viral mitochondrial dysfunction (search) — PubMed: PQQ chronic fatigue post-viral
  5. PQQ and dose timing (search) — PubMed: PQQ dose timing
  6. Magnesium and sleep (search) — PubMed: magnesium and sleep
  7. Mitochondrial dysfunction in long-COVID brain fog (search) — PubMed: long-COVID mitochondrial dysfunction
  8. Suprachiasmatic nucleus mitochondria and circadian function (search) — PubMed: SCN mitochondria circadian

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Research Papers: NGF Synthesis & Neuroprotection

  1. Aizenman E, Hartnett KA, Zhong C, Gallop PM, Rosenberg PA (1992). Interaction of the putative essential nutrient pyrroloquinoline quinone with the N-methyl-D-aspartate receptor redox modulatory site. Journal of Neuroscience 12:2362-9 — PubMed PMID: 1318959
  2. Murase K, Hattori A, Kohno M, Hayashi K (1993). Stimulation of nerve growth factor synthesis/secretion in mouse astroglial cells by coenzymes. Biochemistry and Molecular Biology International 30:615-21 — PubMed PMID: 8401318
  3. Zhang Y, Feustel PJ, Kimelberg HK (2006). Neuroprotection by pyrroloquinoline quinone (PQQ) in reversible middle cerebral artery occlusion in the adult rat. Brain Research 1094:200-6 — PubMed PMID: 16709402
  4. Kim J, Kobayashi M, Fukuda M, et al. (2010). Pyrroloquinoline quinone inhibits the fibrillation of amyloid proteins. Prion 4:26-31 — PubMed PMID: 20083898
  5. Zhao L, Gong N, Liu M, et al. (2014). Beneficial synergistic effects of microdose lithium with pyrroloquinoline quinone in an Alzheimer's disease mouse model. Neurobiology of Aging 35:2736-45 — PubMed PMID: 25018109
  6. Lion's mane (Hericium erinaceus) hericenones and NGF — PubMed: lion's mane NGF
  7. Memantine NMDA mechanism (search) — PubMed: memantine NMDA Alzheimer's
  8. Neurotrophic factors in cognitive aging — PubMed: neurotrophic factors cognitive aging

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Research Papers: Cross-Cutting (Forms, Safety, Mechanism)

  1. Duine JA, Frank J, van Zeeland JK (1979). Glucose dehydrogenase from Acinetobacter calcoaceticus: a 'quinoprotein'. FEBS Letters 108:443-6 — PubMed PMID: 520586
  2. Mitchell AE, Jones AD, Mercer RS, Rucker RB (1999). Characterization of pyrroloquinoline quinone amino acid derivatives by electrospray ionization mass spectrometry and detection in human milk. Analytical Biochemistry 269:317-25 — PubMed PMID: 10222004
  3. Kasahara T, Kato T (2003). Nutritional biochemistry: A new redox-cofactor vitamin for mammals. Nature 422:832 — PubMed PMID: 12712191 (disputed: see the two 2005 comments below)
  4. Felton LM, Anthony C (2005). Biochemistry: role of PQQ as a mammalian enzyme cofactor? Nature 433:E10 — PubMed PMID: 15689995
  5. Rucker R, Storms D, Sheets A, Tchaparian E, Fascetti A (2005). Biochemistry: is pyrroloquinoline quinone a vitamin? Nature 433:E10-1 — PubMed PMID: 15689994
  6. Rucker R, Chowanadisai W, Nakano M (2009). Potential physiological importance of pyrroloquinoline quinone. Alternative Medicine Review 14:268-77 (source of the test-tube "catalytic cycles" figures; one author from a PQQ manufacturer) — PubMed PMID: 19803551
  7. Harris CB, Chowanadisai W, Mishchuk DO, Satre MA, Slupsky CM, Rucker RB (2013). Dietary pyrroloquinoline quinone (PQQ) alters indicators of inflammation and mitochondrial-related metabolism in human subjects. Journal of Nutritional Biochemistry 24:2076-84 — PubMed PMID: 24231099
  8. Nakano M, Takahashi H, Koura S, Chung C, Tafazoli S, Roberts A (2014). Acute and subchronic toxicity studies of pyrroloquinoline quinone (PQQ) disodium salt (BioPQQ™) in rats. Regulatory Toxicology and Pharmacology 70:107-21 — PubMed PMID: 24995591
  9. EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA); Turck D, Bresson JL, Burlingame B, et al. (2017). Safety of pyrroloquinoline quinone disodium salt as a novel food pursuant to Regulation (EC) No 258/97. EFSA Journal 15:e05058 — PubMed PMID: 32625350
  10. PQQ disodium salt vs free acid bioavailability (search) — PubMed: PQQ disodium bioavailability
  11. PQQ with CoQ10 / ubiquinol (search) — PubMed: PQQ with ubiquinol
  12. PQQ in fertility / oocyte mitochondrial quality (search) — PubMed: PQQ oocyte fertility

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External Authoritative Resources

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Connections

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