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

## TL;DR

This study shows that a seizure-causing mutation in fruit flies alters metabolism and that adding a specific fatty acid helps normalize some of these changes.

## Contribution

The study reveals how a sodium channel mutation causes metabolic changes in flies and how dietary α-linolenic acid can partially reverse them.

## Key findings

- The paraShu mutation caused metabolic stress, mitochondrial dysfunction, and redox imbalance in flies.
- Dietary α-linolenic acid partially restored key metabolites and improved redox homeostasis.
- The mutation altered amino acid and nucleotide metabolism, including tryptophan pathways and cyclic nucleotides.

## 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 paraShu, 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 paraShu seizure phenotypes. Adult wild-type and paraShu females were reared on control or ALA-supplemented diets, and 172 metabolites were quantified using GC-MS and LC-MS. The paraShu 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.

The online version contains supplementary material available at 10.1007/s11064-026-04673-2.