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 indicate 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.

CelloMOF: Nanocellulose Enabled 3D Printing of Metal–Organic Frameworks

“…The peak corresponding to the carboxylate groups of TOCNF at 1600 cm −1 broadens and shifts to a lower wavenumber, which could be related to the interaction of ZIF‐8 with carboxylate groups . In the spectra of CelloZIF8s and CelloZIF8‐Curs, the presence of imidazole molecule is associated with the emergence of peaks around 1580 cm −1 (CN stretch mode), bands at 1300–1500 cm −1 (entire ring stretching) and 2904 cm −1 due to the aliphatic CH stretch of the imidazole . The ZnN stretch mode at 421 cm −1 as well as the peak at 748 cm −1 are assigned to out‐of‐plane bending of the ring, which clearly confirms the presence of ZIF‐8 in the ink.…”

Metabolic Dysfunction in Parkinson’s Disease: Bioenergetics, Redox Homeostasis and Central Carbon Metabolism

“…Supplementation of cells with Coenzyme Q 10 (ubiquinone), an electron carrier in the ETC, protects against the toxicity of Complex I inhibitors that block the electron flow from NADH dehydrogenase to Coenzyme Q [2]. Similarly, directly delivery of electrons from NADH to cytochrome c using methylene blue attenuates dopaminergic neurodegeneration induced by rotenone [345]. Importantly, because a 50% inhibition of Complex I is required to cause significant ATP depletion, and Complex I activity is only reduced by 25–30% in PD, ATP depletion might as well not be the single causative event for dopaminergic neurodegeneration [77, 284].…”

Chronic arsenic intoxication diagnostic score (CAsIDS)

“…Approaches to boost mitochondrial bioenergetics (Szalárdy, Zádori, Klivényi, Toldi, & Vécsei, ), including boosting the pyruvate dehydrogenase activity by thiamine (Costantini et al, ) and magnesium (Lonsdale, ) as well as using methylene blue as an alternative mitochondrial electron transfer (Yang et al, ) await experimental and clinical testing. The use of exogenous and endogenous antioxidants (Chan & Chan, ; Kulkarni & Cantó, ) is also a concept that deserves experimental and clinical verification.…”