Propionate increases neuronal histone acetylation, but is metabolized oxidatively by glia. Relevance for propionic acidemia

  title={Propionate increases neuronal histone acetylation, but is metabolized oxidatively by glia. Relevance for propionic acidemia},
  author={Nga H. T. Nguyen and Cecilie Morland and Susana Villa Gonzalez and Frode Rise and Jon Storm-Mathisen and Vidar Gundersen and Bj{\o}rnar Hassel},
  journal={Journal of Neurochemistry},
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: [3‐14C]propionate injected into mouse striatum or cortex, gave a specific activity of glutamine that… 

Propionate enters GABAergic neurons, inhibits GABA transaminase, causes GABA accumulation and lethargy in a model of propionic acidemia.

It is concluded that propionate-induced inhibition of GABA transaminase causes accumulation of GABA in the brain, leading to increased extracellular GABA concentration, which inhibits neuronal activity and causes lethargy.

Impact of Propionic Acidemia on Brain Astrocytes

The involvement of astrocytes from PCCA deficient mice show surprisingly little alterations both in vitro and in vivo, which evidence the need to further understand the effects of PA in brain cells to help develop potential new therapies that can preserve brain function in children affected by this devastating disease.

Glial Metabolism of Isoleucine

NMR analysis of 13C-labelled metabolites generated in the catabolism of [U-13C]Ile by astrocytes and released by them into the incubation medium show that APC can release into the extracellular milieu catabolites and several TCA cycle dependent metabolites resulting from the degradation of isoleucine.

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

The mechanism of heptanoate metabolism in the normal and glucosedeficient brain is enlightened and further studies are encouraged to elucidate its potential antiepileptic effects in disorders of energy metabolism.

Modulation of mitochondrial function by the microbiome metabolite propionic acid in autism and control cell lines

It is demonstrated that enteric microbiome metabolites such as PPA can have both beneficial and toxic effects on mitochondrial function, depending on concentration, exposure duration and microenvironment redox state with these effects amplified in LCLs derived from individuals with ASD.

Enteric Bacterial Metabolites Propionic and Butyric Acid Modulate Gene Expression, Including CREB-Dependent Catecholaminergic Neurotransmission, in PC12 Cells - Possible Relevance to Autism Spectrum Disorders

The data are consistent with a molecular mechanism through which gut related environmental signals such as increased levels of SCFA's can epigenetically modulate cell function further supporting their role as environmental contributors to ASD.

Spontaneous Network Events Driven by Depolarizing GABA Action in Neonatal Hippocampal Slices are Not Attributable to Deficient Mitochondrial Energy Metabolism

The main conclusions of this work are that the inhibitory effect of l-lactate on GDPs is not mediated by mitochondrial energy metabolism, and that glucose at its standard 10 mm concentration is an adequate energy substrate for neonatal neurons in vitro.

Butyrate enhances mitochondrial function during oxidative stress in cell lines from boys with autism

Butyrate (BT) is a ubiquitous short-chain fatty acid (SCFA) principally derived from the enteric microbiome. BT positively modulates mitochondrial function, including enhancing oxidative

Behavioural and brain ultrastructural changes following the systemic administration of propionic acid in adolescent male rats. Further development of a rodent model of autism

Brief systemic administration of this dietary and enteric short chain fatty acid produced behavioural and dynamic brain ultrastructural changes, providing further validation of the PPA model of ASD.



Effect of Propionic Acid on Fatty Acid Oxidation and Ureagenesis

Propionic acid inhibited ureagenesis in rat liver slices when ammonia was the substrate but not with aspartate and citrulline as substrates and raises the possibility that other short chain fatty acids less unusual than 4-pentenoic acid could produce the features of Reye's syndrome.

Trafficking of Amino Acids between Neurons and Glia In Vivo. Effects of Inhibition of Glial Metabolism by Fluoroacetate

The C-3/C-4 enrichment ratio, which indicates the degree of cycling of label, was higher in glutamine than in glutamate in the presence of fluoroacetate, suggesting that transmitter glutamate (which was converted to glutamine after release) is associated with a tricarboxylic acid cycle that turns more rapidly than the overall cerebraltricar boxylic Acid cycle.

Propionic Acid Induces Cytoskeletal Alterations in Cultured Astrocytes From Rat Cerebral Cortex

Results indicate that PA lead to cytoskeletal reorganization and to increased in vitro phosphorylation of Triton-insoluble GFAP and vimentin and these findings could be involved in the brain damage characteristic of propionic acidemia patients.

Interaction of carnitine and propionate with pyruvate oxidation by hepatocytes from clofibrate-treated rats: importance of coenzyme A availability.

  • E. Brass
  • Biology
    The Journal of nutrition
  • 1992
The smaller inhibitory effect of propionate in hepatocytes from clofibrate-treated rats occurred despite increased cellular propionyl-CoA content as compared with controls, but was associated with increased CoASH and total CoA contents and may limit the efficacy of carnitine under conditions of acyl- CoA accumulation.

Propionate Inhibition of Succinate: CoA Ligase (GDP) and the Citric Acid Cycle in Mitochondria

Inhibition of oxidative phosphorylation and the citric acid cycle may produce the Reye's-like syndrome which occurs in propionic acidemia and possibly related organic acid or mitochondrial disorders and Mitochondrial acyl coenzyme A may be increased in these patients and respond favorably to carnitine therapy.

The effect of malate on propionate mitochondrial toxicity.

Pyruvate carboxylation in neurons

  • B. Hassel
  • Biology, Computer Science
    Journal of neuroscience research
  • 2001
Pyruvate carboxylation through malic enzyme is active during energy deficiency and leads to an increase in the level of dicarboxylates that can be metabolized through the tricar boxylic acid cycle for ATP production, and may be one mechanism through which treatment is effective.

Neuronal Pyruvate Carboxylation Supports Formation of Transmitter Glutamate

It is shown that cultured cerebellar granule neurons form releasable [14C]glutamate from H14CO3− and [1- 14C]pyruvate via pyruVate carboxylation, probably mediated by malic enzyme, and thus entails a revision of the current view of glial–neuronal interactions and the importance of the glutamine cycle.

Selective inhibition of glial cell metabolism in vivo by fluorocitrate