Investigating the Role of Mitochondrial Autophagy in Iron-Dependent Cell Death Induced by n-Hexane Exposure

Neurodegenerative diseases serve as the primary focus of this investigation. n-Hexane, a highly volatile and lipophilic solvent, is widely employed in industrial processes, including electronic cleaning, synthetic rubber production, and paint manufacturing. Occupational exposure to n-hexane occurs primarily through inhalation and dermal contact, leading to its hepatic metabolism into the toxic metabolite 2,5-hexanedione (HD), subsequently causing the development of sensory-motor peripheral neuropathy. Previous research suggests that HD exposure triggers neuroinflammatory responses, characterized by neuronal infiltration and elevated levels of inflammatory markers, such as malondialdehyde (MDA), indicating a possible role for lipid peroxidation in regulating neuroinflammation during HD-induced neurotoxicity. However, the precise mechanisms underlying HD-induced neuroinflammation remain elusive.

Iron-dependent cell death has emerged as a prominent area of focus in etiological research and treatment strategies over the past decade. It represents a non-apoptotic form of cell death governed by iron and reactive oxygen species (ROS), influenced by iron metabolism, redox homeostasis, mitochondrial quality control, and various disease-associated signaling pathways. In the context of HD treatment, the activation of microglial inflammatory responses stimulates mitochondrial autophagy, leading to the release of ROS and upregulation of cellular iron levels. Concurrently, the release of inflammatory factors such as TNF-α, IL-6, and IL-1β promotes the upregulation of iron uptake proteins and downregulation of the iron export protein FPN-1. These processes collectively exacerbate neuronal iron overload and lipid peroxidation, ultimately culminating in cell death.

Mitochondria, pivotal organelles involved in cellular growth, metabolism, and signaling, have garnered significant attention in the investigation of the mechanisms underlying neurodegenerative diseases. Mitophagy, a selective autophagic process responsible for eliminating damaged mitochondria, has been implicated in the pathogenesis of neurosensory-motor disorders, often accompanied by genetic mutations in mitochondrial DNA (mtDNA) and robust activation of the NLRP3 inflammasome. Our previous findings demonstrate that HD induces excessive production of mitochondrial ROS in BV2 cells, resulting in impaired mitochondrial function and dysregulated mitophagy, alongside increased expression of NLRP3 and associated inflammatory factors. Importantly, these effects can be mitigated by the administration of the mitochondrial autophagy inhibitor mito-TEMPO.

Studies have provided evidence for the critical regulatory role of mitophagy in iron-dependent cell death during the development of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and age-related macular degeneration (AMD). However, to the best of our knowledge, no reports have yet explored the involvement of mitochondrial autophagy-mediated iron-dependent cell death in HD-induced neurotoxicity.