title: Oxaloacetate activates brain mitochondrial biogenesis, enhances the insulin pathway, reduces inflammation and stimulates neurogenesis.
abstract: Brain bioenergetic function declines in some neurodegenerative diseases, this may influence other pathologies and administering bioenergetic intermediates could have therapeutic value. To test how one intermediate, oxaloacetate (OAA) affects brain bioenergetics, insulin signaling, inflammation and neurogenesis, we administered intraperitoneal OAA, 1-2 g/kg once per day for 1-2 weeks, to C57Bl/6 mice. OAA altered levels, distributions or post-translational modifications of mRNA and proteins (proliferator-activated receptor-gamma coactivator 1α, PGC1 related co-activator, nuclear respiratory factor 1, transcription factor A of the mitochondria, cytochrome oxidase subunit 4 isoform 1, cAMP-response element binding, p38 MAPK and adenosine monophosphate-activated protein kinase) in ways that should promote mitochondrial biogenesis. OAA increased Akt, mammalian target of rapamycin and P70S6K phosphorylation. OAA lowered nuclear factor κB nucleus-to-cytoplasm ratios and CCL11 mRNA. Hippocampal vascular endothelial growth factor mRNA, doublecortin mRNA, doublecortin protein, doublecortin-positive neuron counts and neurite length increased in OAA-treated mice. (1)H-MRS showed OAA increased brain lactate, GABA and glutathione thereby demonstrating metabolic changes are detectable in vivo. In mice, OAA promotes brain mitochondrial biogenesis, activates the insulin signaling pathway, reduces neuroinflammation and activates hippocampal neurogenesis.
authors.affiliation: Department of Neurology, University of Kansas Alzheimer's Disease Center.
authors.forename: Heather M
authors.initials: HM
authors.lastname: Wilkins
authors.affiliation: Hoglund Brain Imaging Center.
authors.forename: Janna L
authors.initials: JL
authors.lastname: Harris
authors.affiliation: University of Kansas Alzheimer's Disease Center.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Carl
authors.affiliation: Department of Rehabilitation Medicine.
authors.forename: Lezi
authors.initials: L
authors.lastname: E
authors.affiliation: Department of Neurology.
authors.forename: Jianghua
authors.initials: J
authors.lastname: Lu
authors.affiliation: Department of Molecular and Integrative Physiology.
authors.forename: J
authors.initials: J
authors.lastname: Eva Selfridge
authors.affiliation: Department of Molecular and Integrative Physiology.
authors.forename: Nairita
authors.initials: N
authors.lastname: Roy
authors.affiliation: University of Kansas Alzheimer's Disease Center.
authors.forename: Lewis
authors.initials: L
authors.lastname: Hutfles
authors.affiliation: University of Kansas Alzheimer's Disease Center.
authors.forename: Scott
authors.initials: S
authors.lastname: Koppel
authors.affiliation: Department of Neurology, University of Kansas Alzheimer's Disease Center.
authors.forename: Jill
authors.initials: J
authors.lastname: Morris
authors.affiliation: Department of Neurology, University of Kansas Alzheimer's Disease Center, Department of Molecular and Integrative Physiology.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Burns
authors.affiliation: University of Kansas Alzheimer's Disease Center, Department of Pharmacology and Toxicology, University of Kansas, Lawrence, KS 66045, USA.
authors.forename: Mary L
authors.initials: ML
authors.lastname: Michaelis
authors.affiliation: University of Kansas Alzheimer's Disease Center, Department of Pharmacology and Toxicology, University of Kansas, Lawrence, KS 66045, USA.
authors.forename: Elias K
authors.initials: EK
authors.lastname: Michaelis
authors.affiliation: Department of Neurology, University of Kansas Alzheimer's Disease Center, Hoglund Brain Imaging Center.
authors.forename: William M
authors.initials: WM
authors.lastname: Brooks
authors.affiliation: Department of Neurology, University of Kansas Alzheimer's Disease Center, Department of Molecular and Integrative Physiology, Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, KS 66160, USA and rswerdlow@kumc.edu.
authors.forename: Russell H
authors.initials: RH
authors.lastname: Swerdlow
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D000089622:Doublecortin Domain Proteins; D003576:Electron Transport Complex IV / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D005978:Glutathione / Q000378:metabolism; D006609:High Mobility Group Proteins / Q000235:genetics / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D007249:Inflammation / Q000517:prevention & control; D007274:Injections, Intraperitoneal; D007328:Insulin / Q000235:genetics / Q000378:metabolism*; D019344:Lactic Acid / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D063269:Mitochondrial Turnover / Q000187:drug effects* / Q000235:genetics; D055495:Neurogenesis / Q000187:drug effects* / Q000235:genetics; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism; D051266:Nuclear Respiratory Factor 1 / Q000235:genetics / Q000378:metabolism; D062907:Oxaloacetic Acid / Q000008:administration & dosage*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D000089622:Doublecortin Domain Proteins; D006609:High Mobility Group Proteins; D007328:Insulin; D008869:Microtubule-Associated Proteins; D009479:Neuropeptides; C495634:Nrf1 protein, mouse; D051266:Nuclear Respiratory Factor 1; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; C081930:Tfam protein, mouse; D014157:Transcription Factors; C111264:peroxisome-proliferator-activated receptor-gamma coactivator-1; D062907:Oxaloacetic Acid; D019344:Lactic Acid; D005680:gamma-Aminobutyric Acid; D003576:Electron Transport Complex IV; D048051:p38 Mitogen-Activated Protein Kinases; D055372:AMP-Activated Protein Kinases; D005978:Glutathione