Polymer-specific nanoplastics trigger oxidative stress, inflammatory activation, and mitoepigenetic remodeling: in vitro and in silico evidence for MT-ND6-mediated mitochondrial complex I perturbation.

INTRODUCTION: Recent studies have detected nanoplastics (NPs) in human tissues and biological fluids, raising concerns regarding their potential effects on cellular homeostasis. Nevertheless, their effects on mitochondrial regulation and mitoepigenetic processes remain poorly understood. This work aimed to study the polymer-specific effects of NPs, including polystyrene (PS), polypropylene (PP), and polyvinyl chloride (PVC), on mitochondrial function, mitochondrial homeostasis, oxidative stress generation, inflammatory response, and mitoepigenetics. METHODS: Cell uptake of NPs was examined using flow cytometry and fluorescence microscopy. Analysis of mitochondrial membrane potential (Δψm), oxidative phosphorylation (OXPHOS), Mitochondrial reactive oxygen species (mtROS) generation, respiratory chain complexes, DNA damage repair enzymes, DNA methylation-related markers, inflammatory cytokines, and mitochondrial gene expression was performed at different time points after NP treatment. Moreover, docking analysis was performed to investigate the potential interactions between oxidized nanoplastic-derived oligomers and mitochondrial Complex I. The relationship between respiratory chain function and mtDNA expression was analyzed using regression. RESULTS: The observed effects of the tested NPs included specific effects of each polymer type, such as increased mtROS production, reduced Δψm, induction of oxidative DNA damage, dysregulation of mitochondrial dynamics, and activation of inflammatory pathways. The stress response was characterized by downregulation of DNA methyltransferases, changes in methylation marker levels, and alterations in mitochondrial gene expression. Functional analysis identified Complex I as particularly vulnerable to the effects of NP treatment. The correlation study demonstrated the coordinated regulation of stress-response mediators in mitochondria, namely, DRP1, OMA1, DELE1, and MT-ND6. Meanwhile, the regression analysis showed a correlation between MT-ND6 expression and Complex I activity. DISCUSSION: Collectively, these findings suggest that environmentally relevant NPs elicit polymer-dependent mitochondrial stress responses, mitoepigenetic remodeling, and inflammatory activation.