Autism Spectrum Disorder: High-Resolution Elucidation of Mitochondrial Dysregulation in Larval Zebrafish Gut

Although gastrointestinal distress is both common and debilitating in individuals with autism spectrum disorder (ASD), underpinning mechanisms-and therefore effective management strategies-are not fully elucidated. The current study employed well-established valproic acid ASD model in larval zebrafish to more comprehensively characterize mitochondrial dysregulation. Whole body redox status and mitochondrial respiration, as well as protein expression in the mitophagy-lysosomal axis in the mid-intestine was assessed. In addition, high-resolution microscopy of the gut was used to assess mitochondrial morphometrics and distribution. Redox imbalance was evident from increased oxygen radical levels and decreased endogenous antioxidant capacity, as well as depression of whole body mitochondrial respiration. Upregulation of endo-lysosomal pathway markers (Rab5, LAMP1) together with reduced expression in mitophagy and autophagy markers (PINK1, LC3B) suggests a potential impairment of canonical mitophagy in the ASD-like gut. High-resolution imaging further revealed smaller, more circular mitochondria, indicative of a morphological fission bias. Abnormal mitochondrial distribution patterns were also evident. Together, current data points to primary mitochondrial dysfunction as a potential feature of the ASD-like gut. Furthermore, data suggest potential insufficiencies in mitochondrial recycling as potential role player in ASD-associated (gut) mitochondrial pathology.