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Editorial
. 2020 Jun:6:100044.
doi: 10.1016/j.medidd.2020.100044. Epub 2020 May 11.

Melatonin Inhibits COVID-19-induced Cytokine Storm by Reversing Aerobic Glycolysis in Immune Cells: A Mechanistic Analysis

Russel J Reiter  1 , Ramaswamy Sharma  1 , Qiang Ma  1 , Alberto Dominquez-Rodriguez  2 , Paul E Marik  3 , Pedro Abreu-Gonzalez  4
Affiliations
Editorial

Melatonin Inhibits COVID-19-induced Cytokine Storm by Reversing Aerobic Glycolysis in Immune Cells: A Mechanistic Analysis

Russel J Reiter et al. Med Drug Discov. 2020 Jun.
No abstract available

Keywords: COVID-19; Melatonin; Warburg effect; respiratory system; viral infection.

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Figures

Fig. 1
Fig. 1
This figure illustrates the differential glucose metabolism in a healthy macrophage and in a COVID-19-activated macrophage. In a healthy macrophage, pyruvate, a glucose metabolite, enters the mitochondria where it is enzymatically converted to acetyl-coenzyme A by the enzyme pyruvate dehydrogenase complex (PDC). Acetyl-coenzyme A feeds the tricarboxylic acid cycle (TCA) and supports oxidative phosphorylation (OXPHOS). Additionally, acetyl-coenzyme A is an essential co-factor/substrate for the rate limiting enzyme in melatonin synthesis, arylalkylamine N-acetyltransferase (AANAT). This allows for melatonin to be regularly produced in healthy macrophages; melatonin functions intracellularly and is released into the cellular microenvironment, but not into the blood. In COVID-19-activated mitochondria, via HIF-1α, mTOR, etc., the enzyme pyruvate dehydrogenase kinase (PDK) is strongly upregulated and inhibits PDC (red X). Thus, acetyl-coenzyme A is not synthesized and mitochondrial OXPHOS falters with ATP synthesis occurring in the cytosol via aerobic glycolysis (Warburg effect). Similarly, mitochondrial melatonin production is shut down so the cell is deprived of an essential antioxidant, anti-inflammatory agent and of an immune-enhancer so the elevated synthesis of proinflammatory cytokines goes uncontested and the cytokine storm is a result. 5-HT = serotonin; ASMT = acetylserotonin methyltransferase; CoA = coenzyme A; IMM = inner mitochondrial membrane; HIF-1α = hypoxia inducible factor-1α; mTOR = mammalian target of rapamycin; NAS = N-acetylserotonin; OMM = outer mitochondrial membrane; PPP = pentose phosphate pathway.
See this image and copyright information in PMC

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