Work

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

Year: 2026

Type: article

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 para Shu , 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 para Shu 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.

Source: Neurochemical Research

DOI: 10.1007/s11064-026-04673-2

Authors: Karina Kruth, Junko Kasuya, Victoria Hand, Atulya Iyengar, Toshihiro Kitamoto

Institutions: University of Iowa, University of Iowa Health Care, University of Alabama

Language: English

Topic: Epilepsy research and treatment

Subfield: Psychiatry and Mental health

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $4,590