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.

Kinetic mutations in argininosuccinate synthetase deficiency: characterisation and in vitro correction by substrate supplementation

“…Thus, supplementation with oral oxaloacetate should directly increase the cytosolic aspartate pool since, as already mentioned, GOT1 and glutamate are available in this cell compartment (figure 1). For these reasons, we propose the evaluation of oxaloacetate as a novel treatment option for patients with citrullinemia type 1 with decreased affinity for aspartate since, on the one hand, it is the direct precursor of cytosolic aspartate, and on the other hand, is an available medical food used as a glutamate scavenger for brain protection31 32 and a nutritional supplement widely used both as anti-ageing33 and brain stimulating agents 34. To evaluate the suitability of using oxaloacetate, it should be tested first in fibroblasts from patients carrying a kinetic mutation and then in vivo by measuring the ureagenesis rate in presence and absence of oxaloacetate, for instance in one of the two currently available citrullinemia type 1 hypomorphic mouse models35 and lastly, in a subset of patients with citrullinemia type 1 carrying a kinetic mutation.…”

Extracellular Mitochondria and Mitochondrial Components Act as Damage-Associated Molecular Pattern Molecules in the Mouse Brain

“…RNA was isolated, cDNA synthesized, and qPCR completed as previously described (Wilkins et al 2014). mRNA levels were measured using primers to the following: amyloid precursor protein ( App ), C-C motif chemokine ligand 11 ( Ccl11 ), cluster of differentiation molecule 11b ( Cd11B ), colony stimulating factor 1 ( Csf1 ), colony stimulating factor receptor 1 ( Csf1r ), glial fibrillary acidic protein ( Gfap ), interleukin 1β ( Il1β ), interleukin 1 receptor ( Il1r ), triggering receptor expressed on myeloid cells 2 ( Trem2 ), and tumor necrosis factor α ( Tnfα ).…”

“…Cortex was dissected from the RNA Later-preserved tissue and processed as previously described (Busciglio et al 2002; Wilkins et al 2014). Western blots were completed using the following antibodies: AKT/protein kinase B (Cell Signaling, 1:1000), pAKT Ser 473 (Cell Signaling 1:500), pAKT Thr308 (Cell Signaling, 1:500), actin (Cell Signaling, 1:2000), APP (Cell Signaling, 1:1000), CSF1R (Cell Signaling, 1:500), glial fibrillary acidic protein (GFAP) (Abcam, 1:1000), histone deacetylase 1 (HDAC1, Cell Signaling 1:2000), nuclear factor kappa-light-chain-enhancer of activated B cells (NF B) p65 (Cell Signaling, 1:1000), and pNF B p65-Ser 536 (Abcam, 1:500).…”

“…Paraformaldehyde-preserved tissue was prepared, sectioned, stained, and quantified as previously described (Wilkins et al 2014). The following antibodies and reagents were used for IHC: GFAP (Abcam 1:500), secondary antibody donkey anti-rabbit AlexaFlour 488 (Abcam 1:500), and ProLong Gold Antifade reagent with DAPI (ThermoFisher).…”

Trends in Mitochondrial Therapeutics for Neurological Disease

“…A tentative pre-clinical evaluation of the bioenergetic intermediate oxaloacetate, as potential treatment for AD and other neurodegenerative disorders, reported increased PGC-1α mRNA, activated mitochondrial biogenesis and hippocampal neurogenesis in C57Bl/6 mice [108].…”