Autism-Linked Gene NRXN1 Found to Affect Mitochondrial Energy and Metabolism: Preclinical Findings

Synopsis

Autism is often linked to differences in language, social interaction, and repetitive behaviors, but it is increasingly recognized that energy metabolism and mitochondrial dysfunction can also be involved. In fruit flies, the autism-associated gene NRXN1, called Nrx-1 in Drosophila, was found to regulate energy metabolism and nutrient balance. Flies lacking Nrx-1 were less able to survive nutrient deprivation or heat stress, had lower lipid and carbohydrate stores, and showed reduced levels of NAD+, a key coenzyme in energy pathways. These flies also had abnormal mitochondrial structure in their flight muscles, impaired flight ability, and seizure-like activity after mechanical shock, reflecting metabolic and neurological defects linked to NRXN1 deletions in humans. Treating Nrx-1 mutants with NAD+ precursors, nicotinamide riboside (NR) or NAM, did not restore their resistance to starvation, and in some cases worsened it, suggesting that reduced NAD+ alone may not fully explain the metabolic problems, and that dosage, timing, or additional factors may influence the phenotype.

Journal

Human Molecular Genetics