Alternative mitochondrial electron transfer as a novel strategy for neuroprotection

Yi Wen, Wenjun Li, Ethan C. Poteet, Luokun Xie, Cong Tan, Liang Jun Yan, Xiaohua Ju, Ran Liu, Hai Qian, Marian A. Marvin, Matthew S. Goldberg, Hua She, Zixu Mao, James W. Simpkins, Shao Hua Yang

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Abstract

Neuroprotective strategies, including free radical scavengers, ion channel modulators, and anti-inflammatory agents, have been extensively explored in the last 2 decades for the treatment of neurological diseases. Unfortunately, none of the neuroprotectants has been proved effective in clinical trails. In the current study, we demonstrated that methylene blue (MB) functions as an alternative electron carrier, which accepts electrons from NADH and transfers them to cytochrome c and bypasses complex I/III blockage. A de novo synthesized MB derivative, with the redox center disabled byN-acetylation, had no effect on mitochondrial complex activities. MB increases cellular oxygen consumption rates and reduces anaerobic glycolysis in cultured neuronal cells. MB is protective against various insults in vitro at low nanomolar concentrations. Our data indicate that MB has a unique mechanism and is fundamentally different from traditional antioxidants. We examined the effects of MB in two animal models of neurological diseases. MB dramatically attenuates behavioral, neurochemical, and neuropathological impairment in a Parkinson disease model. Rotenone caused severe dopamine depletion in the striatum, which was almost completely rescued by MB. MB rescued the effects of rotenone on mitochondrial complex I-III inhibition and free radical overproduction. Rotenone induced a severe loss of nigral dopaminergic neurons, which was dramatically attenuated by MB. In addition, MB significantly reduced cerebral ischemia reperfusion damage in a transient focal cerebral ischemia model. The present study indicates that rerouting mitochondrial electron transfer by MB or similar molecules provides a novel strategy for neuroprotection against both chronic and acute neurological diseases involving mitochondrial dysfunction.

Original languageEnglish
Pages (from-to)16504-16515
Number of pages12
JournalJournal of Biological Chemistry
Volume286
Issue number18
DOIs
StatePublished - 6 May 2011

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Wen, Y., Li, W., Poteet, E. C., Xie, L., Tan, C., Yan, L. J., Ju, X., Liu, R., Qian, H., Marvin, M. A., Goldberg, M. S., She, H., Mao, Z., Simpkins, J. W., & Yang, S. H. (2011). Alternative mitochondrial electron transfer as a novel strategy for neuroprotection. Journal of Biological Chemistry, 286(18), 16504-16515. https://doi.org/10.1074/jbc.M110.208447