Mechanisms underlying perfluorooctanoic acid-induced neuronal loss and cognitive deficits: Disruption of mitochondrial dynamics, impaired mitophagy, and blood-brain barrier dysfunction.

Perfluorooctanoic acid (PFOA), a persistent member of the Per- and polyfluoroalkyl substances (PFAS), is widely detected in the environment and human populations and has recently been increasingly associated with neurotoxicity; however, its underlying molecular mechanisms, particularly those involving mitochondrial quality control, remain poorly defined. This study aimed to elucidate the mechanistic basis of PFOA-induced neurotoxicity, focusing on mitochondrial dysfunction, dynamics, and mitophagy, and to determine the downstream effects on neuronal integrity and cognitive function using both in-vitro and in-vivo approaches. In N2a cells, PFOA exposure induced significant oxidative stress, characterized by elevated intracellular and mitochondrial ROS levels and loss of mitochondrial membrane potential (Δψm). These alterations were accompanied by dysregulation of mitochondrial dynamics, evidenced by suppression of fusion proteins (MFN1, MFN2, OPA1) and enhanced activation of fission regulators (DRP1, FIS1). Concurrently, mitophagy was impaired, as indicated by dysregulation of PINK1-Parkin and LC3-p62 signaling, suggesting defective mitochondrial clearance. In-vivo, chronic PFOA exposure disrupted blood-brain barrier integrity, as reflected by increased MMP-9 and reduced tight junction proteins (ZO-1, occludin, claudin-5), and was associated with enhanced neuronal apoptosis, histopathological damage, and cognitive deficits. Collectively, these findings demonstrate that PFOA induces neurotoxicity through mitochondrial dysfunction-driven impairment of mitochondrial dynamics and quality control, leading to neuronal degeneration and neurobehavioral dysfunction.