Mitochondrial dysfunction and oxidative stress in autism spectrum disorder: pharmacological insights into natural...

Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders characterized by social communication deficits, restricted and fixated interests and abnormal motor behaviors. Increasing evidence implicates oxidative stress, mitochondrial dysfunction, and neuroinflammation as key biological features of ASD. Aberrant redox homeostasis, reduced glutathione reserves, increased lipid peroxidation, and dysregulated NRF2 signaling have been documented in both peripheral tissues and brain samples. Post-mortem and imaging studies further reveal deficits in electron transport chain complexes and pyruvate dehydrogenase activity, suggesting a mechanistic link between mitochondrial bioenergetics and ASD-related phenotypes. These pathomechanisms have motivated interest in antioxidant metabolites from botanical drugs and nutrients as complementary strategies. To critically appraise mechanisms and levels of evidence (in vitro, in vivo, clinical) for vitamin E and C, glutathione and its precursors, polyphenols (quercetin, resveratrol, curcumin), Crocus sativus carotenoids (crocin/safranal), and "indirect" modulators (e.g., omega-3, folinic acid), emphasizing study quality, translational relevance, and limitations. The aim of this review is to synthesize current findings on the potential benefits of antioxidants in addressing both molecular and behavioral aspects of ASD, while also examining the link between oxidative stress and ASD. Furthermore, we discuss the role of antioxidant-based interventions in managing ASD symptoms. The review highlights the complex challenges associated with antioxidant therapies and deficiencies, emphasizing the need for a multifaceted nutritional approach particularly in children with ASD.