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.

Keywords: Cancer; Metabolism; Methylene blue; Mitochondria electron transport chain; Neurodegeneration.

Figure 1

Energy and mass: from Einstein equation to energy metabolism. Einstein’s famous equation reveals the interchangeable relationship of mass and energy. The significance of Einstein’s formula is even beyond physics. In biology, conversion between mass and energy are fundamental processes defined as metabolism. Through anabolism, complex compounds are biosynthesized from simpler molecules with the energy expense provided by ATP hydrolysis. Through catabolism, complex nutrients are broken down to simpler oxidized compounds with an energy releasing process coupled to ATP production. Life is the interplay between energy and structure. As the metabolism goes on, the life goes on. E: energy. M: mass. C: speed of light.

Figure 2

Function of methylene blue (MB) as an alternative mitochondrial electron transfer carrier and regenerable antioxidant. MB accepts electron from NADH in the presence of complex I. Upon the redox cycle (MB- MBH2-MB), electrons are delivered to cytochrome c in an alternate route despite the inhibition of complex I and III. The distinct redox property enables MB as a regenerable anti-oxidant in mitochondria that distinct from the traditional free radical scavenges.

Figure 3

Methylene blue feeding improved water-maze and bridge walking performance in 5 X FAD mice. Wild type and 5 X FAD female mice were switched to diets containing MB or vehicle at the age of 8 weeks and continually fed for 8 months. At the age of 10 months, the mice were subjected to batteries of behavioral testing of water-maze and bridge walking as described previously (Shetty et al., 2014). MB diet group had significantly reduced average latency to fall in the bridge walking test as compared to control diet group (A). In water-maze test, MB feeding significantly improved learning index (B). All mice were sacrificed and the effect of MB on brain Aβ plaques were determined. MB feeding decreases Aβ plaque evidenced by 6E10 immunohistochemistry (C) and Western blot analysis (D). # p<0.05 vs Control AD. * p<0.05 vs Control wild-type.

Figure 4

Reprograming energetic metabolism for the treatment of neurodegenerative diseases and brain tumor. Metabolic reprograming may serve as a common mechanistic foundation for neurodegenerative diseases and cancers. Accordingly, targeting energy metabolism may provide a one stone two birds strategy for the treatment both neurodegenerative diseases and cancers. While enforcing brain bioenergetics may enhance brain function hence slow down or prevent the progression of neurodegenerative diseases, switching cancer metabolic phenotype from biosynthetic back to bioenergetic might exhaust building brick for cancer biomass, thus, inhibit cancers proliferation.