Melatonin and Pathological Cell Interactions: Mitochondrial Glucose Processing in Cancer Cells

Abstract

Melatonin is synthesized in the pineal gland at night. Since melatonin is produced in the mitochondria of all other cells in a non-circadian manner, the amount synthesized by the pineal gland is less than 5% of the total. Melatonin produced in mitochondria influences glucose metabolism in all cells. Many pathological cells adopt aerobic glycolysis (Warburg effect) in which pyruvate is excluded from the mitochondria and remains in the cytosol where it is metabolized to lactate. The entrance of pyruvate into the mitochondria of healthy cells allows it to be irreversibly decarboxylated by pyruvate dehydrogenase (PDH) to acetyl coenzyme A (acetyl-CoA). The exclusion of pyruvate from the mitochondria in pathological cells prevents the generation of acetyl-CoA from pyruvate. This is relevant to mitochondrial melatonin production, as acetyl-CoA is a required co-substrate/co-factor for melatonin synthesis. When PDH is inhibited during aerobic glycolysis or during intracellular hypoxia, the deficiency of acetyl-CoA likely prevents mitochondrial melatonin synthesis. When cells experiencing aerobic glycolysis or hypoxia with a diminished level of acetyl-CoA are supplemented with melatonin or receive it from another endogenous source (pineal-derived), pathological cells convert to a more normal phenotype and support the transport of pyruvate into the mitochondria, thereby re-establishing a healthier mitochondrial metabolic physiology.

The Effect of β-Carotene, Tocopherols and Ascorbic Acid as Anti-Oxidant Molecules on Human and Animal In Vitro/In Vivo Studies: A Review of Research Design and Analytical Techniques Used

“…Melatonin is a direct ROS scavenger ( 1 O 2 , O 2 • − ,•OH) by donating electron(s) to the ROS, with the formation of products such as cyclic 3-hydroxymelatonin or indolyl radical cation of low reactivity [ 123 ]. Melatonin can be also supplied exogenously from diet or supplements [ 125 ] to heal jet lag, insomnia, narcolepsy and other sleep disorders, and is considered as a potential cardioprotective, anti-inflammatory and anti-cancer agent [ 126 ].…”

A Review of the Potential Effects of Melatonin in Compromised Mitochondrial Redox Activities in Elderly Patients With COVID-19

“…During SARS-CoV-2 infection, viral ORF3a induces HIF-1α activation, which in turn aggravates viral infection and inflammatory responses ( 275 ). Melatonin may attenuate the damage resulting from COVID-19-mediated septicemia by mollifying HIF-1α, suppressing NF-κB, inhibiting the inflammasome, converting pro-inflammatory M1 macrophages to anti-inflammatory M2 macrophages, and reversing Warburg-type metabolism ( 276 – 278 ). After administration as an adjuvant therapy, melatonin was found to attenuate Th1 and Th2 inflammatory cytokines by downregulating the expression of Th1 and Th2 regulatory genes in patients with COVID-19 ( 279 ).…”

Melatonin Reverses the Warburg-Type Metabolism and Reduces Mitochondrial Membrane Potential of Ovarian Cancer Cells Independent of MT1 Receptor Activation

“…Some antitumor characteristics of melatonin are dependent on activation of the MT1 receptor; however, melatonin also exerts intracellular effects that are independent of MT1 [ 4 ]. Previous studies demonstrated that melatonin reaches specific subcellular compartments through the glucose transporter (GLUT1) and human peptide transporter 1 and 2 (PEPT1/2) [ 13 , 14 , 15 ].…”

“…Mitochondria are the organelles responsible for cell metabolic functions such as energy production, pyruvate metabolism, and cellular respiration (oxidative phosphorylation or OXPHOS) [ 15 , 20 ]. Metabolic reprogramming that induces high glycolytic rates even in the presence of oxygen (Warburg effect) is a hallmark of cancer [ 4 , 21 ].…”

“…In addition, acetyl-CoA is a cofactor to the AANAT enzyme which is rate limiting in mitochondrial melatonin synthesis. The reduction in acetyl-CoA levels results in less melatonin for tumor cells and depresses the tricarboxylic acid cycle, which normally supports ATP production [ 15 , 23 ]. Against this background, the present study investigated the influence of melatonin therapy on energy metabolism and mitochondrial physiology in human ovarian carcinoma cells (SKOV-3 cell line) and further examined whether these biological effects are mediated by the MT1 melatonin receptor.…”