Alternative mitochondrial electron transfer for the treatment of neurodegenerative diseases and cancers

Methylene blue connects the dots

Shaohua Yang, Wenjun Li, Nathalie Sumien, Michael J. Forster, James W. Simpkins, Ran Liu

Research output: Contribution to journalReview articleResearchpeer-review

15 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)273-291
Number of pages19
JournalProgress in Neurobiology
Volume157
DOIs
StatePublished - 1 Oct 2017

Fingerprint

Methylene Blue
Neurodegenerative Diseases
Electrons
Energy Metabolism
Oxidative Phosphorylation
Glucose
Glycolysis
Neoplasms
Glioblastoma
Glioma
Cerebrovascular Circulation
Therapeutics
AMP-Activated Protein Kinases
Cyclin-Dependent Kinases
Huntington Disease
Regional Blood Flow
Brain
Cell Cycle Checkpoints
Cytochromes c
Oxygen Consumption

Keywords

  • Cancer
  • Metabolism
  • Methylene blue
  • Mitochondria electron transport chain
  • Neurodegeneration

Cite this

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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.",
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Alternative mitochondrial electron transfer for the treatment of neurodegenerative diseases and cancers : Methylene blue connects the dots. / Yang, Shaohua; Li, Wenjun; Sumien, Nathalie; Forster, Michael J.; Simpkins, James W.; Liu, Ran.

In: Progress in Neurobiology, Vol. 157, 01.10.2017, p. 273-291.

Research output: Contribution to journalReview articleResearchpeer-review

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AU - Li, Wenjun

AU - Sumien, Nathalie

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AU - Simpkins, James W.

AU - Liu, Ran

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