first_pagesettingsOrder Article Reprints Open AccessReview Melatonin and Pathological Cell Interactions: Mitochondrial Glucose Processing in Cancer Cells by Russel J Reiter 1,*ORCID,Ramaswamy Sharma 1,*ORCID,Sergio Rosales-Corral 2,Walter Manucha 3ORCID,Luiz Gustavo de Almeida Chuffa 4ORCID andDebora Aparecida Pires de Campos Zuccari 5ORCID 1 Department of Cell Systems & Anatomy, Joe R. and Teresa Lozano Long School of Medicine, UT Health San Antonio, San Antonio, TX 78229, USA 2 Centro de Investigacion Biomedica de Occidente, Instituto Mexicano del Seguro Social, Guadalajara 45150, Mexico 3 Instituto de Medicina y Biologia Experimental de Cuyo (IMBECU), Consejo Nacional de Investigaciones Cientificas y Tecnologicas (CONICET), Mendoza 5500, Argentina 4 Department of Structural and Functional Biology, Institute of Biosciences of Botucatu, Botucatu 18618-689, Brazil 5 Laboratorio de Investigacao Molecular do Cancer, Faculdade de Medicina de Sao Jose do Rio Preto, Sao Jose do Rio Preto 15080-000, Brazil * Authors to whom correspondence should be addressed. Int. J. Mol. Sci. 2021, 22(22), 12494; https://doi.org/10.3390/ijms222212494 Received: 24 June 2021 / Revised: 6 October 2021 / Accepted: 17 November 2021 / Published: 19 November 2021 (This article belongs to the Special Issue Mitochondrial Functions, Alterations and Dynamics in Cancer) Download Browse Figures Versions Notes 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.