The Role of Mitochondrial Autophagy and Iron-dependent Cell Death in n-Hexane-Induced Neurotoxicity

The Role of Mitochondrial Autophagy and Iron-dependent Cell Death in n-Hexane-Induced Neurotoxicity

This study investigates the potential role of mitochondrial autophagy in mediating iron-dependent cell death within the context of n-hexane-induced neurotoxicity, using neurodegenerative diseases as a background. n-Hexane, a widely used industrial solvent, is metabolized into the neurotoxic compound 2,5-hexanedione (HD), primarily known to induce sensory-motor peripheral neuropathy.

Previous research has established that HD exposure triggers neuroinflammation, characterized by neuronal infiltration and elevated inflammatory markers like malondialdehyde (MDA). This suggests that lipid peroxidation plays a crucial role in regulating neuroinflammation within HD-induced neurotoxicity. However, the exact mechanisms driving HD-induced neuroinflammation remain elusive.

Iron-dependent cell death has emerged as a significant focus in etiological research and treatment strategies over the past decade. This non-apoptotic form of cell death, regulated by iron and reactive oxygen species (ROS), is influenced by iron metabolism, redox homeostasis, mitochondrial quality control, and various disease-related signaling pathways. In the case of HD exposure, microglial inflammatory activation triggers mitochondrial autophagy. This process results in the release of ROS and an increase in iron content, alongside the release of inflammatory factors like TNF-α, IL-6, and IL-1β. These factors, in turn, upregulate iron uptake proteins and downregulate the iron export protein FPN-1, ultimately exacerbating neuronal iron overload, lipid peroxidation, and cell death.

Mitochondria, being central to cellular growth, metabolism, and signaling, have garnered considerable attention in recent years within the realm of neurodegenerative disease mechanisms. Mitophagy, a selective autophagic process responsible for clearing damaged mitochondria, has been implicated in the pathogenesis of neurosensory-motor diseases. These diseases often present with genetic mutations in mtDNA and robust activation of the NLRP3 inflammasome. Our prior research demonstrated that HD induces excessive mitochondrial ROS production in BV2 cells, consequently impairing mitochondrial function, promoting mitophagy, and increasing NLRP3 and related inflammatory factor expression. These effects were mitigated by the mitochondrial autophagy inhibitor mito-TEMPO.

Existing studies highlight the crucial regulatory role of mitophagy in iron-dependent cell death during the development of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and age-related macular degeneration (AMD). However, there is a lack of research investigating the role of mitochondrial autophagy-mediated iron-dependent cell death in HD-induced neurotoxicity. This study aims to address this gap and further elucidate the mechanisms underlying HD-induced neurotoxicity.