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 [ 3 H]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.

Heptanoate as a Neural Fuel: Energetic and Neurotransmitter Precursors in Normal and Glucose Transporter I-Deficient (G1D) Brain

“…34,35 For example, the injection of 14 C-labeled propionate to the striatum or cortex of mice resulted in five to six times higher labeling of glutamine relative glutamate. 34 Ebert et al 35 reported that the metabolism of 13 C-octanoate in the brain occurs predominantly in the glial compartment based on the greater enrichment of glutamine over glutamate. Together, these findings suggest that the potential anticonvulsant effect of triheptanoin may begin or take place primarily in glia.…”

“…12,13,34 It has been hypothesized that, in certain forms of epilepsy, TCA cycle intermediates may be deficient in the context of neuronal hyperexcitability. 11 Willis et al 11 reported that dietary triheptanoin restored malate levels in the brain of pilocarpineinduced status epilepticus mice, who also experienced an increase G1D, glucose transporter type I deficiency; GABA, g-aminobutyric acid; TCA, tricarboxylic acid.…”

“…In carbon 3, the glutamine 13 C resonance was also greater than the glutamate resonance (Figures 3 and 4A), with no difference between animal groups. As it occurred with carbon 2, the labeling pattern was notably different between both molecules: The doublet (D) in carbon 3 can arise due to J 23 or J 34 since the coupling constants are virtually identical. The fractional amount of the glutamine C3 doublet was greater relative to that of glutamate and equivalent in both animals (Po0.001) ( Figure 4C).…”

Carbohydrate quantitative digestion and absorption in ruminants: from feed starch and fibre to nutrients available for tissues

“…Odd-chain fatty acids, in particular propionate, take a different enzymatic pathway leading to succinyl-CoA. Two of the propionate metabolites (propionylCoA and 2-methylcitrate) having inhibitory effects on the Krebs cycle (Nguyen et al, 2007), propionate is largely used as a precursor of gluconeogenesis. Considering the limited absorption of glucose, and the similar whole body glucose requirements in ruminants and monogastrics (Lindsay, 1981), ruminants rely on hepatic gluconeogenesis for 85% of their whole body glucose turnover (Ortigues-Marty et al, 2003a).…”

A Novel Rodent Model of Autism: Intraventricular Infusions of Propionic Acid Increase Locomotor Activity and Induce Neuroinflammation and Oxidative Stress in Discrete Regions of Adult Rat Brain

“…In addition to passive accumulation in CNS cells, there is also evidence that PPA and other short chain fatty acids are specifically taken up by monocarboxylate receptors in cerebrovascular endothelium, neurons and glia [90][91][92] . PPA is metabolized by glial cells which involves the propionyl CoA carboxlyase enzyme [93] . PPA increases the levels of the cytotoxin propionyl CoA and depletes cytosolic carnitine stores leading to a reduction in fatty acid metabolism by mitochondria which can cause further reductions in intracellular pH [50,51] .…”