Exposure to an environmentally relevant mixture of polychlorinated biphenyls affects mitochondrial bioenergetics and plasticity

Abstract

Adaptations of cells to environmental insults typically require tightly regulated processes to preserve the organismal steady state, particularly in metabolically active cells such as neural cells. Polychlorinated biphenyls (PCBs) are persistent organic pollutants widely recognized for their neurotoxic potential. Due to their lipophilic nature, these compounds readily accumulate in the brain, where they can disrupt neuronal homeostasis. Herein, we examined the effects of exposure to an environmentally relevant PCB mixture on mitochondrial dynamics, ultrastructure, and function in the mouse neuroblastoma Neuro2a cell line. Ultrastructural examinations indicated evident signs of mitochondrial damage, including swelling, cristae disruption, and increased frequency of autophagic structures. Quantification of mitochondrial networks confirmed a shift from tubular to fragmented morphologies, accompanied with the modulation of the gene expression of genes involved in mitochondrial fusion and fission. Specifically, mitofusin 2 protein levels were increased at 24 and 48 h of treatment, and OPA1 at 48 h, whereas Drp1, phosphorylated at Ser616 was increased at 24 h. Markers of mitophagy PINK1 and Parkin were elevated at 72 and 48 h of exposure, respectively, whereas Atg5 and Atg7, markers of autophagy were increased at 24 h. We observed a decrease in mitochondrial membrane potential and increase in mtDNA levels in PCB-treated cultures at 24 h. Oxidative stress was also implicated by overexpression and increased enzymatic activity of superoxide dismutase 1 (SOD1). Functional tests revealed a transient impairment of mitochondrial respiration and ATP synthesis, which was later restored, pointing to the recruitment of compensatory mechanisms. Together, these results indicate that PCB exposure activates an integrated stress response with oxidative imbalance, mitochondrial bioenergetics, remodeling, and autophagy features, revealing the neural cell vulnerability and plasticity to environmental insult.