title: Malate-Aspartate Shuttle Inhibitor Aminooxyacetate Acid Induces Apoptosis and Impairs Energy Metabolism of Both Resting Microglia and LPS-Activated Microglia.
abstract: NADH shuttles mediate the transfer of the reducing equivalents of cytosolic NADH into mitochondria. Cumulating evidence has suggested that malate-aspartate shuttle (MAS), one of the two types of NADH shuttles, plays significant roles in such biological processes as glutamate synthesis in neurons. However, there has been no information regarding the roles of NADH shuttle in the survival and energy metabolism of microglia. In current study, using microglial BV2 cells as a cellular model, we determined the roles of MAS in the survival and energy metabolism of microglia by using aminooxyacetate acid (AOAA)-a widely used MAS inhibitor. Our study has suggested that AOAA can effectively inhibit the MAS activity of the cells. We also found that AOAA can induce both early- and late-stage apoptosis of resting microglia and lipopolysaccharides (LPS)-activated microglia. AOAA also induced mitochondrial depolarization, increases in the cytosolic Ca(2+) concentrations, and decreases in the intracellular ATP levels. Moreover, our study has excluded the possibility that the major nonspecific effect of AOAA-inhibition of GABA transaminase-is involved in theses effects of AOAA. Collectively, our study has provided first information suggesting significant roles of MAS in the survival and energy metabolism in both resting microglia and LPS-activated microglia.
authors.affiliation: Med-X Research Institute, School of Biomedical Engineering, Shanghai Jiao Tong University, 1954 Huashan Road, Shanghai, 200030, People's Republic of China.
authors.forename: Heyu
authors.initials: H
authors.lastname: Chen
authors.forename: Caixia
authors.initials: C
authors.lastname: Wang
authors.forename: Xunbin
authors.initials: X
authors.lastname: Wei
authors.forename: Xianting
authors.initials: X
authors.lastname: Ding
authors.forename: Weihai
authors.initials: W
authors.lastname: Ying
mesh_terms: D000612:4-Aminobutyrate Transaminase / Q000037:antagonists & inhibitors; D000255:Adenosine Triphosphate / Q000378:metabolism; D000625:Aminooxyacetic Acid / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001224:Aspartic Acid / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D004734:Energy Metabolism / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation / Q000187:drug effects; D008293:Malates / Q000378:metabolism*; D051379:Mice; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D008293:Malates; D000625:Aminooxyacetic Acid; D001224:Aspartic Acid; C030298:malic acid; D000255:Adenosine Triphosphate; D007770:L-Lactate Dehydrogenase; D000612:4-Aminobutyrate Transaminase; D053148:Caspase 3; D002118:Calcium