title: Dysregulation of glutamine transporter SNAT1 in Rett syndrome microglia: a mechanism for mitochondrial dysfunction and neurotoxicity.
abstract: Rett syndrome (RTT) is an autism spectrum disorder caused by loss-of-function mutations in the gene encoding MeCP2, an epigenetic modulator that binds the methyl CpG dinucleotide in target genes to regulate transcription. Previously, we and others reported a role of microglia in the pathophysiology of RTT. To understand the mechanism of microglia dysfunction in RTT, we identified a MeCP2 target gene, SLC38A1, which encodes a major glutamine transporter (SNAT1), and characterized its role in microglia. We found that MeCP2 acts as a microglia-specific transcriptional repressor of SNAT1. Because glutamine is mainly metabolized in the mitochondria, where it is used as an energy substrate and a precursor for glutamate production, we hypothesize that SNAT1 overexpression in MeCP2-deficient microglia would impair the glutamine homeostasis, resulting in mitochondrial dysfunction as well as microglial neurotoxicity because of glutamate overproduction. Supporting this hypothesis, we found that MeCP2 downregulation or SNAT1 overexpression in microglia resulted in (1) glutamine-dependent decrease in microglial viability, which was corroborated by reduced microglia counts in the brains of MECP2 knock-out mice; (2) proliferation of mitochondria and enhanced mitochondrial production of reactive oxygen species; (3) increased oxygen consumption but decreased ATP production (an energy-wasting state); and (4) overproduction of glutamate that caused NMDA receptor-dependent neurotoxicity. The abnormalities could be rectified by mitochondria-targeted expression of catalase and a mitochondria-targeted peptide antioxidant, Szeto-Schiller 31. Our results reveal a novel mechanism via which MeCP2 regulates bioenergetic pathways in microglia and suggest a therapeutic potential of mitochondria-targeted antioxidants for RTT.
authors: Department of Pathology and Laboratory Medicine and M.I.N.D. (Medical Investigation of Neurodevelopmental Disorders) Institute, University of California Davis Medical Center, Sacramento, California 95817.
authors: Lee-Way
authors: LW
authors: Jin
authors: Department of Pathology and Laboratory Medicine and.
authors: Makoto
authors: M
authors: Horiuchi
authors: Departments of Pharmacology and.
authors: Heike
authors: H
authors: Wulff
authors: Department of Pathology and Laboratory Medicine and.
authors: Xiao-Bo
authors: XB
authors: Liu
authors: Molecular Biosciences, University of California Davis, Davis, California 95618, and.
authors: Gino A
authors: GA
authors: Cortopassi
authors: Neuroscience Center, Louisiana State University Health Science Center, New Orleans, Louisiana 70118.
authors: Jeffrey D
authors: JD
authors: Erickson
authors: Department of Pathology and Laboratory Medicine and M.I.N.D. (Medical Investigation of Neurodevelopmental Disorders) Institute, University of California Davis Medical Center, Sacramento, California 95817, imaezawa@ucdavis.edu.
authors: Izumi
authors: I
authors: Maezawa
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D026924:Amino Acid Transport System A / Q000378:metabolism*; D000818:Animals; D018698:Glutamic Acid / Q000378:metabolism; D005998:Glycine / Q000378:metabolism; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism*; D028361:Mitochondrial Diseases / Q000378:metabolism*; D020258:Neurotoxicity Syndromes / Q000378:metabolism*; D010101:Oxygen Consumption / Q000502:physiology; D061251:Primary Cell Culture; D015518:Rett Syndrome / Q000378:metabolism*
chemical_list: D026924:Amino Acid Transport System A; C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2; C432411:Slc38a1 protein, mouse; D018698:Glutamic Acid; D000255:Adenosine Triphosphate; D005998:Glycine
keywords: Rett; glutamate; glutamine; microglia; mitochondria; transporter