# Effects of a Gain-of-Function Mutation in the Voltage-Gated Sodium Channel Gene, and of Dietary α-Linolenic Acid Supplementation, on Whole-Body Metabolism in Drosophila

## TL;DR

This study shows how a genetic mutation in fruit flies causes metabolic changes linked to epilepsy, and how adding a specific fatty acid to their diet can help reduce these effects.

## Contribution

The study reveals a novel link between sodium-channel hyperexcitability and metabolic reprogramming in a Drosophila model of epilepsy.

## Key findings

- The paraShu mutation alters central carbon metabolism, indicating mitochondrial dysfunction and reduced NADPH output.
- Dietary ALA supplementation partially normalizes metabolic imbalances and improves redox buffering.
- Microbially-derived fatty acids suggest interactions between gut microbiota and host metabolism in the mutant model.

## Abstract

Epilepsy is a prevalent neurological disorder, and metabolic disturbances are increasingly recognized as key contributors to seizure susceptibility. We profiled whole-body metabolism in the precisely defined, seizure-prone Drosophila mutant paraShu, carrying a gain-of-function mutation in the voltage-gated sodium channel gene, and assessed the modulatory impact of dietary α-linolenic acid (ALA). Adult wild-type and mutant females were raised on control or ALA-supplemented diets, and untargeted GC-MS/LC-MS was used to quantify 172 metabolites. The paraShu mutation led to robust shifts in central carbon metabolism, including increases in glycolytic end products and decreases in TCA and pentose phosphate pathway intermediates. Both outcomes are indicative of mitochondrial dysfunction and reduced NADPH output. Critically, levels of nicotinamide riboside and its derivative nicotinic acid adenine dinucleotide were decreased. This suggests that NAD+ biosynthesis was constrained and/or its turnover accelerated. Amino acid networks—particularly those involving tryptophan metabolism—were reorganized in a way that supports NAD+ balance and redox regulation, and nucleotide pools were unbalanced. Analysis of fatty-acids revealed high levels of microbially-derived short-chain fatty acids (SCFAs) and medium-chain species, indicative of gut-host interactions. Treatment with ALA partially normalized levels of SCFAs, succinate, 6-phosphogluconate, glycine, and proline, and increased levels of N-methylnicotinamide, consistent with improved redox buffering and dampened signaling by the innate immune pathway. Overall, our data indicate that sodium-channel hyperexcitability elicits coordinated metabolic reprogramming that links mitochondrial dysfunction with redox imbalance and interactions between microbiota and immune pathways, and that dietary ALA lessen these changes. The affected pathways represent testable targets for mechanism-based epilepsy interventions.