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Mitochondrial Electron Transport Chain Complex Dysfunction in MeCP2 Knock-Down Astrocytes: Protective Effects of Quercetin Hydrate.

Journal of molecular neuroscience : MN (2018-12-07)
Arpita Dave, Foram Shukla, Hemendra Wala, Prakash Pillai
ABSTRACT

Astrocytes play the central role in CNS metabolism to support neuronal functions. Mehyl-CpG-binding protein 2 (MeCP2) is the global transcription factor with differential expression in neuronal and non-neuronal cells. MeCP2 mutation and downstream detrimental effects have been reported in astrocytes also in MeCP2-associated neurodevelopmental disorder-Rett syndrome. Several studies have shown mitochondrial impairment linked to ROS production and reduced ATP synthesis in Rett patients and models, but consequences of MeCP2 deficiency on mitochondrial electron transport chain complexes in astrocytes and effect of known antioxidant quercetin aglycone has not yet been reported. The present study aimed to investigate effect of quercetin on mitochondrial functioning in MeCP2-deficient astrocytes. Our data show onefold upregulated Uqcrc1 and Ndufv2 gene expression, subtle change in protein expression, and significantly reduced mitochondrial respiratory chain complex-II and complex-III enzyme activities in MeCP2 knock-down astrocytes. Intracellular calcium robustly increased and mitochondrial membrane potential decreased, while no change in ROS was observed in MeCP2 knock-down astrocytes. Quercetin increased MeCP2 and normalized Uqcrc1 and Ndufv2 gene expression but did not modulate MeCP2 and Ndufv2 proteins expression. Interestingly, quercetin upregulated significantly the mitochondrial respiratory complex-II, complex-III, and complex-IV activities in dose-dependent manner. It also restored intracellular calcium level and mitochondrial membrane potential. In vitro observations suggest the beneficial effect of quercetin in mitochondrial functioning in MeCP2-deficient condition. There are no reports focusing on role of quercetin in mitochondrial function in MeCP2-deficient astrocytes, and these observations serve as preliminary data to evaluate quercetin's effects in vivo.