title: Alternative mitochondrial electron transfer for the treatment of neurodegenerative diseases and cancers: Methylene blue connects the dots.
abstract: Brain has exceptional high requirement for energy metabolism with glucose as the exclusive energy source. Decrease of brain energy metabolism and glucose uptake has been found in patients of Alzheimer's, Parkinson's and other neurodegenerative diseases, providing a clear link between neurodegenerative disorders and energy metabolism. On the other hand, cancers, including glioblastoma, have increased glucose uptake and rely on aerobic glycolysis for energy metabolism. The switch of high efficient oxidative phosphorylation to low efficient aerobic glycolysis pathway (Warburg effect) provides macromolecule for biosynthesis and proliferation. Current research indicates that methylene blue, a century old drug, can receive electron from NADH in the presence of complex I and donates it to cytochrome c, providing an alternative electron transfer pathway. Methylene blue increases oxygen consumption, decrease glycolysis, and increases glucose uptake in vitro. Methylene blue enhances glucose uptake and regional cerebral blood flow in rats upon acute treatment. In addition, methylene blue provides protective effect in neuron and astrocyte against various insults in vitro and in rodent models of Alzheimer's, Parkinson's, and Huntington's disease. In glioblastoma cells, methylene blue reverses Warburg effect by enhancing mitochondrial oxidative phosphorylation, arrests glioma cell cycle at s-phase, and inhibits glioma cell proliferation. Accordingly, methylene blue activates AMP-activated protein kinase, inhibits downstream acetyl-coA carboxylase and cyclin-dependent kinases. In summary, there is accumulating evidence providing a proof of concept that enhancement of mitochondrial oxidative phosphorylation via alternative mitochondrial electron transfer may offer protective action against neurodegenerative diseases and inhibit cancers proliferation.
authors.affiliation: Center for Neuroscience Discovery, University of North Texas Health Science Center, Fort Worth, TX 76107, USA. Electronic address: shaohua.yang@unthsc.edu.
authors.forename: Shao-Hua
authors.initials: SH
authors.lastname: Yang
authors.affiliation: Center for Neuroscience Discovery, University of North Texas Health Science Center, Fort Worth, TX 76107, USA.
authors.forename: Wenjun
authors.initials: W
authors.lastname: Li
authors.affiliation: Center for Neuroscience Discovery, University of North Texas Health Science Center, Fort Worth, TX 76107, USA.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Sumien
authors.affiliation: Center for Neuroscience Discovery, University of North Texas Health Science Center, Fort Worth, TX 76107, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Forster
authors.affiliation: Department of Physiology and Pharmacology, Center for Neuroscience, Health Science Center, West Virginia University, Medical Center Drive, Morgantown, WV 26506, USA.
authors.forename: James W
authors.initials: JW
authors.lastname: Simpkins
authors.affiliation: Center for Neuroscience Discovery, University of North Texas Health Science Center, Fort Worth, TX 76107, USA.
authors.forename: Ran
authors.initials: R
authors.lastname: Liu
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004579:Electron Transport / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D008751:Methylene Blue / Q000494:pharmacology* / Q000627:therapeutic use; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000188:drug therapy* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D018696:Neuroprotective Agents; D008751:Methylene Blue
keywords: Cancer; Metabolism; Methylene blue; Mitochondria electron transport chain; Neurodegeneration