TY - JOUR
T1 - Alternative mitochondrial electron transfer for the treatment of neurodegenerative diseases and cancers
T2 - Methylene blue connects the dots
AU - Yang, Shao Hua
AU - Li, Wenjun
AU - Sumien, Nathalie
AU - Forster, Michael
AU - Simpkins, James W.
AU - Liu, Ran
N1 - Funding Information:
This work was partly supported by National Institutes of Health grants R01NS054651 (SY), R01NS088596 (SY), American Heart Association grant SDG16960084 (RL).
Publisher Copyright:
© 2015 Elsevier Ltd
PY - 2017/10
Y1 - 2017/10
N2 - 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.
AB - 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.
KW - Cancer
KW - Metabolism
KW - Methylene blue
KW - Mitochondria electron transport chain
KW - Neurodegeneration
UR - http://www.scopus.com/inward/record.url?scp=84966282818&partnerID=8YFLogxK
U2 - 10.1016/j.pneurobio.2015.10.005
DO - 10.1016/j.pneurobio.2015.10.005
M3 - Review article
C2 - 26603930
AN - SCOPUS:84966282818
SN - 0301-0082
VL - 157
SP - 273
EP - 291
JO - Progress in Neurobiology
JF - Progress in Neurobiology
ER -