Russel J. Reiter,a,⁎ Ramaswamy Sharma,a Qiang Ma,a Alberto Dominquez-Rodriguez,b Paul E. Marik,c and Pedro Abreu-Gonzalezd
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A number of drugs have been proposed as treatments to prevent or reduce the severity of a COVID-19 infection. One agent that has been suggested to be potentially useful in this regard is the endogenously synthesized molecule, melatonin [[3], [4], [5], [6], [7]]. Melatonin was initially discovered in and thought to be exclusively a product of the vertebrate pineal gland. However, in consideration of the identification of melatonin in prokaryotic bacteria [8], from which mitochondria evolved (the endosymbiotic theory) and the uncommonly high levels of assayable melatonin in mitochondria [9], it was speculated and eventually documented that this indoleamine is synthesized in this organelle [10]. Given that most cells (a few exceptions) contain mitochondria, it is now believed that melatonin production occurs in most cells in all organisms. This has also been specifically demonstrated in human lung monocytes/macrophages [11].
In healthy cells, including macrophages, melatonin synthesis in mitochondria is maintained by the entrance of pyruvate, a glucose metabolite, into the mitochondria where it is metabolized to acetyl-coenzyme A by the enzyme, pyruvate dehydrogenase complex (PDC). Acetyl-coenzyme A feeds the citric acid cycle and supports ATP synthesis, but it is also a required co-factor/substrate for the rate limiting enzyme in melatonin synthesis, arylalkylamine N-acetyltransferase (AANAT) (Fig. 1). Thus, when mitochondria adopt aerobic glycolysis, pyruvate in mitochondria is no longer converted to acetyl-coenzyme A because PDC is inhibited by the enzyme pyruvate dehydrogenase kinase (PDK); Therefore, as a consequence of a COVID-19 infection the macrophage mitochondria cannot synthesize melatonin [12].
Because of melatonin’s potent antioxidant and anti-inflammatory activities, it would normally reduce the highly proinflammatory cytokine storm and neutralize the generated free radicals thereby preserving cellular integrity and preventing lung damage. In the absence of acetyl-coenzyme A, mitochondrial melatonin is no longer available to combat the inflammatory response or to neutralize the generated reactive oxygen species and the massive damage that occurs in the respiratory tree resulting in the primary signs of COVID-19 disease. Importantly, endogenous melatonin production diminishes markedly with age especially in frail older individuals. This is consistent with the more serious nature of a COVID-19 infection in the elderly.
Aerobic glycolysis is an important feature of highly proinflammatory state since it ensures the necessary high levels of ATP and the abundant supply of biomolecules to ensure synthesis and release of the damaging molecules that constitute the cytokine storm. This increased aerobic glycolysis coupled with the absence of locally-produced melatonin provides the optimal environment (the perfect “cytokine storm”) for the massive tissue damage that occurs in COVID-19 disease.
Given the above information, the use of supplemental melatonin as a treatment to overcome a COVID-19 infection is justified. Exogenously administered melatonin reverses aerobic glycolysis by repressing both HIF-1α and mTOR thereby disinhibiting PDC activity and allowing acetyl-coenzyme A synthesis which also ensures locally-produced melatonin production [13]. The functionally re-instated mitochondria-generated melatonin in combination with the parenteral melatonin provides a formidable weapon to reduce the cytokine storm as well as its damaging consequences thereby relieving the signs of a COVID-19 infection.
The anti-inflammatory and antioxidant actions of melatonin in protecting the lungs from damage in many experimental models that involve inflammation or oxidative stress (or both) is well documented [14]. Moreover, melatonin has anti-viral actions against viruses other than COVID-19 [15,16]. The collective data, in addition to its very high safety profile, indicate that melatonin would be effective as a treatment for COVID-19 and support the recommendation of the published reports that encourage its use for this purpose [[3], [4], [5], [6], [7]]. Melatonin is inexpensive, non-toxic over a very wide dose range, has a long shelf-life and can be self-administered which is a major advantage when large numbers of individuals are involved. Thus, the use of melatonin to mitigate the COVID-19 pandemic would be feasible and a socially-responsible measure to attempt.
Acknowledgments
Not applicable.
Conflict of Interest
The authors declare no conflict of interest.
Authors’ contributions
All authors participated in discussions related to melatonin and COVID-19. The first draft of the manuscript was written by RJR; the paper was then reviewed and edited by all co-authors. The final version of the report was read and approved by all co-authors.
Funding
The authors received no funding to support this publication.
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