Mitochondria, real powerhouses of the cells, are crucial for energy production and cellular health. Their impairment leads to oxidative stress, inflammation, and energy deficits, contributing to the development of brain diseases. This article explores an emerging therapeutic approach using methylene blue, a chemical targeting mitochondria, and offering new hope for treating neurological disorders.
The Role of Mitochondria in Energy Production
Mitochondria are essential organelles in eukaryotic cells that produce energy in the form of adenosine triphosphate (ATP) via oxidative phosphorylation of glucose. Mitochondria have a double membrane structure with five complexes in their inner membrane involved in ATP production and forming the respiratory chain [1].
Complexes I (NADH-ubiquinone oxidoreductase) and II (succinate-ubiquinone oxidoreductase) are the main entrance points for electrons generated from NADH and FADH2 transfer [2]. These electrons then flow down an electrochemical gradient, shuttled by complexes III (CoQ-cytochrome c reductase) and IV (cytochrome c oxidase) and two mobile carriers, ubiquinone and cytochrome c [3]. While transporting electrons, each complex pumps a proton (H+) through the inner membrane into the intermembrane space, creating a proton gradient, which allows complex V (ATP synthase) to phosphorylate ADP and generate ATP [4].
This process is highly efficient. However, electrons can escape from complexes I and III, leading to the reduction of oxygen (O₂) to form the superoxide anion radical (O₂•−), a highly reactive chemical member of the reactive oxygen species (ROS) family [5]. The superoxide anion radical then triggers the formation of other ROS, including hydrogen peroxide (H2O2), a hydroxyl radical (HO•) [6], and peroxynitrite (ONOO−) [7] that can damage cellular proteins and lipids [7,8].
Mitochondrial Dysfunction in Neurological Disorders
ROS production is enhanced under pathological conditions, particularly in the brain (which consumes more energy than any other organ [9]), and promotes inflammation. This vicious cycle that links ROS production, inflammation, and neuronal damage are key processes implicated in a wide range of neurological disorders [10]. The mitochondrial imbalance, characterized by energy deficits and excessive ROS production, takes part in the pathophysiology of many diseases, such as Parkinson’s disease, Alzheimer’s disease, traumatic brain injury, and stroke [11-13].
While the etiology and progression of neurological disorders differ, mitochondrial dysfunction is shared by all [7]. Therefore, rescuing mitochondrial function (ensuring metabolic activity and ROS generation remain within physiologically normal ranges) emerges as a promising strategy to treat neurodegeneration and other brain disorders [14-16].
Methylene Blue’s Role in Mitochondria
Methylene blue, also known as 3,7-bis(dimethylamino)-phenothiazin-5-ium chloride or methylthioninium chloride, is an FDA-approved medication for treating methemoglobinemia [17] and is also used as a dye during surgery [18]. Methylene blue is a powerful antioxidant that crosses the brain-blood barrier, shows a strong affinity for mitochondria, and targets mitochondrial respiration. These properties suggest that methylene blue may treat neurological disorders efficiently [15,19-22].
Methylene blue demonstrates beneficial effects in numerous neurological disorders (including frontotemporal dementia, Alzheimer’s disease, Parkinson’s disease, stroke, and traumatic brain injury) through various mechanisms [7]. Notably, its therapeutic impact partly comes from its unique ability to alternate between reduced and oxidized forms and act as an alternative electron carrier in the mitochondrial respiratory chain [23]. Indeed, methylene blue can accept electrons from NADH via complex I, converting itself into leucomethylene blue. In turn, leucomethylene blue passes these electrons to cytochrome c oxidase (complex IV), efficiently bypassing complexes I and III. During this process, leucomethylene blue is re-oxidized back into methylene blue, allowing it to re-enter and repeat the cycle. Thus, methylene blue prevents electron leaking, promotes mitochondrial oxidative phosphorylation through cytochrome c oxidase activation, and reduces ROS production. In other words, methylene blue increases oxygen consumption and ATP formation while attenuating oxidative stress [12].
Therapeutic Potential of Methylene Blue via Cytochrome C Oxidase
Alzheimer’s disease
Mitochondrial dysfunction appears before plaque deposition and cognitive decline in Alzheimer’s disease (AD) [24]. The amyloid-β protein, known to form neuritic plaques in AD, co-localizes in the mitochondria and disrupts the respiratory chain at complexes III and IV [7,25]. In a rat model of streptozotocin-induced AD, methylene blue rescued cytochrome c oxidase activity and ATP production while decreasing ROS, as evidenced by reduced cognitive deficits in those rats [20]. In other animal models of AD, methylene blue treatment improved cognitive performance [26,27]. Similarly, in clinical trials with patients with mild to moderate AD, methylene blue treatment enhanced cognitive function and cerebral blood flow [28].
Ischemic brain injury and stroke
Neurons affected by hypoperfusion, ischemic brain injury or stroke experience reduced availability of glucose and oxygen, impairing mitochondrial function and leading to disrupted ATP production and increased ROS. Methylene blue was neuroprotective in several ischemic injury and stroke models thanks to its antioxidant properties and ability to act as an alternative mitochondrial transfer [7]. The mechanism underlying methylene blue efficacy via cytochrome c oxidase, validated in a rat model of stroke, was increased O2 consumption, cytochrome c oxidase activity, and ATP production [14].
Hepatic encephalopathy
Mitochondrial impairment, specifically reduced cytochrome c oxidase activity, is a key factor in hepatic encephalopathy. In a rat model, methylene blue treatment improved cognitive functions by increasing cytochrome c oxidase activity [29].
Conclusion
Mitochondrial dysfunction is central to many neurological disorders. Methylene blue, acting as an electron carrier, can restore mitochondrial respiration by bypassing complexes I and III and enhancing cytochrome c oxidase activity. As a result, mitochondria increase oxygen consumption and ATP formation while reducing ROS production and oxidative stress. Consequently, methylene blue demonstrates therapeutic potential to treat several neurological disorders.
If you're looking for ways to optimize your mitochondrial function and energy production, read here, or you can check out our two methylene blue products at Troscriptions: Just Blue and Tro+ Blue.
Just Blue (16 mg of methylene blue) will brighten your focus, decrease inflammation, and boost your energy and endurance, while Tro+ Blue (50 mg of methylene blue) was designed for practitioners because its dosing is a very powerful anti-infective, anti-inflammatory, and mitochondrial rescue.
References
[1] Kühlbrandt, W. (2015) Structure and function of mitochondrial membrane protein complexes. BMC Biology, 13, 89. https://doi.org/10.1186/s12915-015-0201-x
[2] Nolfi-Donegan, D., Braganza, A. and Shiva, S. (2020) Mitochondrial electron transport chain: Oxidative phosphorylation, oxidant production, and methods of measurement. Redox Biology, 37, 101674. https://doi.org/10.1016/j.redox.2020.101674
[3] Berry, E.A., Guergova-Kuras, M., Huang, L. and Crofts, A.R. (2000) Structure and Function of Cytochrome bc Complexes. Annual Review of Biochemistry, 69, 1005–75. https://doi.org/10.1146/annurev.biochem.69.1.1005
[4] Cooper, G.M. (2000) The cell: a molecular approach. 2nd ed. ASM Press, Washington, D.C. Sunderland, Mass.
[5] Auchter, A.M., Barrett, D.W., Monfils, M.H. and Gonzalez-Lima, F. (2020) Methylene Blue Preserves Cytochrome Oxidase Activity and Prevents Neurodegeneration and Memory Impairment in Rats With Chronic Cerebral Hypoperfusion. Frontiers in Cellular Neuroscience, 14, 130. https://doi.org/10.3389/fncel.2020.00130
[6] Collin, F. (2019) Chemical Basis of Reactive Oxygen Species Reactivity and Involvement in Neurodegenerative Diseases. International Journal of Molecular Sciences, 20, 2407. https://doi.org/10.3390/ijms20102407
[7] Tucker, D., Lu, Y. and Zhang, Q. (2018) From Mitochondrial Function to Neuroprotection-an Emerging Role for Methylene Blue. Molecular Neurobiology, 55, 5137–53. https://doi.org/10.1007/s12035-017-0712-2
[8] Andrés, C.M.C., Pérez De La Lastra, J.M., Andrés Juan, C., Plou, F.J. and Pérez-Lebeña, E. (2023) Superoxide Anion Chemistry—Its Role at the Core of the Innate Immunity. International Journal of Molecular Sciences, 24, 1841. https://doi.org/10.3390/ijms24031841
[9] Sokoloff, L., Reivich, M., Kennedy, C., Rosiers, M.H.D., Patlak, C.S., Pettigrew, K.D. et al. (1977) THE [14 C]DEOXYGLUCOSE METHOD FOR THE MEASUREMENT OF LOCAL CEREBRAL GLUCOSE UTILIZATION: THEORY, PROCEDURE, AND NORMAL VALUES IN THE CONSCIOUS AND ANESTHETIZED ALBINO RAT1. Journal of Neurochemistry, 28, 897–916. https://doi.org/10.1111/j.1471-4159.1977.tb10649.x
[10] Chaturvedi, R.K. and Flint Beal, M. (2013) Mitochondrial Diseases of the Brain. Free Radical Biology and Medicine, 63, 1–29. https://doi.org/10.1016/j.freeradbiomed.2013.03.018
[11] Hoyer, S. (1991) Abnormalities of Glucose Metabolism in Alzheimer’s Disease. Annals of the New York Academy of Sciences, 640, 53–8. https://doi.org/10.1111/j.1749-6632.1991.tb00190.x
[12] Lin, A.-L., Poteet, E., Du, F., Gourav, R.C., Liu, R., Wen, Y. et al. (2012) Methylene Blue as a Cerebral Metabolic and Hemodynamic Enhancer. Chen K, editor. PLoS ONE, 7, e46585. https://doi.org/10.1371/journal.pone.0046585
[13] Dash, U.C., Bhol, N.K., Swain, S.K., Samal, R.R., Nayak, P.K., Raina, V. et al. (2024) Oxidative stress and inflammation in the pathogenesis of neurological disorders: Mechanisms and implications. Acta Pharmaceutica Sinica B, S2211383524004040. https://doi.org/10.1016/j.apsb.2024.10.004
[14] Ahmed, M.E., Tucker, D., Dong, Y., Lu, Y., Zhao, N., Wang, R. et al. (2016) Methylene Blue promotes cortical neurogenesis and ameliorates behavioral deficit after photothrombotic stroke in rats. Neuroscience, 336, 39–48. https://doi.org/10.1016/j.neuroscience.2016.08.036
[15] Bhat, A.H., Dar, K.B., Anees, S., Zargar, M.A., Masood, A., Sofi, M.A. et al. (2015) Oxidative stress, mitochondrial dysfunction and neurodegenerative diseases; a mechanistic insight. Biomedicine & Pharmacotherapy, 74, 101–10. https://doi.org/10.1016/j.biopha.2015.07.025
[16] Chen, X., Guo, C. and Kong, J. (2012) Oxidative stress in neurodegenerative diseases. Neural Regeneration Research, 7, 376–85. https://doi.org/10.3969/j.issn.1673-5374.2012.05.009
[17] Wright, R.O., Lewander, W.J. and Woolf, A.D. (1999) Methemoglobinemia: Etiology, Pharmacology, and Clinical Management. Annals of Emergency Medicine, 34, 646–56. https://doi.org/10.1016/S0196-0644(99)70167-8
[18] Cwalinski, T., Polom, W., Marano, L., Roviello, G., D’Angelo, A., Cwalina, N. et al. (2020) Methylene Blue—Current Knowledge, Fluorescent Properties, and Its Future Use. Journal of Clinical Medicine, 9, 3538. https://doi.org/10.3390/jcm9113538
[19] Huang, L., Lu, J., Cerqueira, B., Liu, Y., Jiang, Z. and Duong, T.Q. (2018) Chronic oral methylene blue treatment in a rat model of focal cerebral ischemia/reperfusion. Brain Research, 1678, 322–9. https://doi.org/10.1016/j.brainres.2017.10.033
[20] Li, L., Qin, L., Lu, H., Li, P.-J., Song, Y.-J. and Yang, R.-L. (2017) Methylene blue improves streptozotocin-induced memory deficit by restoring mitochondrial function in rats. Brain Research, 1657, 208–14. https://doi.org/10.1016/j.brainres.2016.12.024
[21] Hosokawa, M., Arai, T., Masuda-Suzukake, M., Nonaka, T., Yamashita, M., Akiyama, H. et al. (2012) Methylene Blue Reduced Abnormal Tau Accumulation in P301L Tau Transgenic Mice. LeBlanc AC, editor. PLoS ONE, 7, e52389. https://doi.org/10.1371/journal.pone.0052389
[22] Necula, M., Breydo, L., Milton, S., Kayed, R., Van Der Veer, W.E., Tone, P. et al. (2007) Methylene Blue Inhibits Amyloid Aβ Oligomerization by Promoting Fibrillization. Biochemistry, 46, 8850–60. https://doi.org/10.1021/bi700411k
[23] Atamna, H. and Kumar, R. (2010) Protective Role of Methylene Blue in Alzheimer’s Disease via Mitochondria and Cytochrome c Oxidase. Zhu X, Beal MF, Wang X, Perry G, and Smith MA, editors. Journal of Alzheimer’s Disease, 20, S439–52. https://doi.org/10.3233/JAD-2010-100414
[24] Yao, J., Irwin, R.W., Zhao, L., Nilsen, J., Hamilton, R.T. and Brinton, R.D. (2009) Mitochondrial bioenergetic deficit precedes Alzheimer’s pathology in female mouse model of Alzheimer’s disease. Proceedings of the National Academy of Sciences, 106, 14670–5. https://doi.org/10.1073/pnas.0903563106
[25] Chen, J.X. and Yan, S.D. (2007) Amyloid-beta-induced mitochondrial dysfunction. Journal of Alzheimer’s Disease: JAD, 12, 177–84. https://doi.org/10.3233/jad-2007-12208
[26] Medina, D.X., Caccamo, A. and Oddo, S. (2011) Methylene Blue Reduces Aβ Levels and Rescues Early Cognitive Deficit by Increasing Proteasome Activity. Brain Pathology, 21, 140–9. https://doi.org/10.1111/j.1750-3639.2010.00430.x
[27] Hochgräfe, K., Sydow, A., Matenia, D., Cadinu, D., Könen, S., Petrova, O. et al. (2015) Preventive methylene blue treatment preserves cognition in mice expressing full-length pro-aggregant human Tau. Acta Neuropathologica Communications, 3, 25. https://doi.org/10.1186/s40478-015-0204-4
[28] Wischik, C.M., Staff, R.T., Wischik, D.J., Bentham, P., Murray, A.D., Storey, J.M.D. et al. (2015) Tau Aggregation Inhibitor Therapy: An Exploratory Phase 2 Study in Mild or Moderate Alzheimer’s Disease. Journal of Alzheimer’s Disease, 44, 705–20. https://doi.org/10.3233/JAD-142874
[29] Méndez, M., Fidalgo, C., Arias, J.L. and Arias, N. (2021) Methylene blue and photobiomodulation recover cognitive impairment in hepatic encephalopathy through different effects on cytochrome c-oxidase. Behavioural Brain Research, 403, 113164. https://doi.org/10.1016/j.bbr.2021.113164
Comments (0)
There are no comments for this article. Be the first one to leave a message!