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Metabolic Alterations Induced by a Seizure-Causing Sodium Channel Mutation and their Partial Normalization by Dietary α-Linolenic Acid in Drosophila
Journal article   Open access   Peer reviewed

Metabolic Alterations Induced by a Seizure-Causing Sodium Channel Mutation and their Partial Normalization by Dietary α-Linolenic Acid in Drosophila

Karina Kruth, Junko Kasuya, Victoria Hand, Atulya Iyengar and Toshihiro Kitamoto
Neurochemical research, Vol.51(1), 51
01/20/2026
DOI: 10.1007/s11064-026-04673-2
PMCID: PMC12819498
PMID: 41557249
Appears in  UI Libraries Support Open Access
url
https://doi.org/10.1007/s11064-026-04673-2View
Published (Version of record) Open Access

Abstract

Epilepsy is increasingly recognized as a disorder with prominent metabolic disturbances, but how defined epilepsy-causing mutations reshape metabolism under controlled genetic and environmental conditions remains poorly understood. Here, we used the Drosophila melanogaster gain-of-function voltage-gated sodium channel (VGSC) mutant para , a well-established model of neuronal and behavioral hyperexcitability, to characterize whole-body metabolic alterations and their modulation by dietary supplementation with the ω-3 polyunsaturated fatty acid α-linolenic acid (ALA), which strongly and specifically suppresses para seizure phenotypes. Adult wild-type and para females were reared on control or ALA-supplemented diets, and 172 metabolites were quantified using GC-MS and LC-MS. The para mutation induced broad metabolic alterations, including enhanced glycolysis, reduced tricarboxylic acid cycle and pentose phosphate pathway intermediates, and depletion of nicotinamide riboside and nicotinic acid adenine dinucleotide, suggesting metabolic stress, mitochondrial dysfunction, and impaired redox balance. Amino acid and nucleotide metabolism were extensively reorganized, with prominent changes in tryptophan pathways, as well as imbalances in purine and pyrimidine nucleotides and cyclic nucleotides (cAMP, cGMP). Levels of microbially derived short-chain fatty acids and indole derivatives were elevated, implicating altered gut-brain metabolic interactions. Dietary ALA partially normalized key metabolites, including succinate, 6-phosphogluconate, glycine, proline, and short-chain fatty acids, and increased N-methylnicotinamide, consistent with improved redox homeostasis and attenuated inflammation. These findings demonstrate that VGSC-driven hyperexcitability elicits coordinated metabolic and microbiota-related changes, and that ALA can mitigate these disturbances, highlighting testable metabolic targets for mechanism-based interventions in epilepsy.
 alpha-Linolenic Acid - administration & dosage alpha-Linolenic Acid - pharmacology alpha-Linolenic Acid - therapeutic use Animals Drosophila melanogaster Drosophila Proteins - genetics Female Mutation - genetics Seizures - diet therapy Seizures - genetics Seizures - metabolism Voltage-Gated Sodium Channels - genetics UIOWA OA Agreement

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