title: Propionate increases neuronal histone acetylation, but is metabolized oxidatively by glia. Relevance for propionic acidemia.
abstract: In propionic acidemia, propionate acts as a metabolic toxin in liver cells by accumulating in mitochondria as propionyl-CoA and its derivative, methylcitrate, two tricarboxylic acid cycle inhibitors. Little is known about the cerebral metabolism of propionate, although clinical effects of propionic acidemia are largely neurological. We found that propionate was metabolized oxidatively by glia: [3-(14)C]propionate injected into mouse striatum or cortex, gave a specific activity of glutamine that was 5-6 times that of glutamate, indicating metabolism in cells that express glutamine synthetase, i.e., glia. Further, cultured cerebellar astrocytes metabolized [3-(14)C]propionate; cultured neurons did not. However, both cultured cerebellar neurons and astrocytes took up [3H]propionate, and propionate exposure increased histone acetylation in cultured neurons and astrocytes as well as in hippocampal CA3 pyramidal neurons of wake mice. The inability of neurons to metabolize propionate may be due to lack of mitochondrial propionyl-CoA synthetase activity or transport of propionyl residues into mitochondria, as cultured neurons expressed propionyl-CoA carboxylase, a mitochondrial matrix enzyme, and oxidized isoleucine, which becomes converted into propionyl-CoA intramitochondrially. The glial metabolism of propionate suggests astrocytic vulnerability in propionic acidemia when intramitochondrial propionyl-CoA may accumulate. Propionic acidemia may alter both neuronal and glial gene expression by affecting histone acetylation.
authors.affiliation: Norwegian Defence Research Establishment, Kjeller, Norway.
authors.forename: Nga H T
authors.initials: NH
authors.lastname: Nguyen
authors.forename: Cecilie
authors.initials: C
authors.lastname: Morland
authors.forename: Susana Villa
authors.initials: SV
authors.lastname: Gonzalez
authors.forename: Frode
authors.initials: F
authors.lastname: Rise
authors.forename: Jon
authors.initials: J
authors.lastname: Storm-Mathisen
authors.forename: Vidar
authors.initials: V
authors.lastname: Gundersen
authors.forename: Bjørnar
authors.initials: B
authors.lastname: Hassel
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000378:metabolism; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology; D005260:Female; D006657:Histones / Q000378:metabolism*; D007554:Isotopes / Q000493:pharmacokinetics; D051379:Mice; D008954:Models, Biological; D009457:Neuroglia / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects*; D011422:Propionates / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D013997:Time Factors
chemical_list: D006657:Histones; D007554:Isotopes; D011422:Propionates