Conserved and particle-specific mitochondrial stress responses drive immunotoxicity of ultrafine particulate matter, black carbon, and polystyrene nanoplastics

Introduction Several studies have examined human exposure to ultrafine particulate matter (UFPM), Black carbon (BC), and polystyrene nanoplastics (PS-NPs). However, it remains unclear whether different chemical types of environmental nanoparticles induce a similar mitochondrial stress response or a unique particle-specific response. Methods In the present study, we examined the molecular mechanisms underlying nanoparticle-induced mitochondrial stress response and immunotoxicity using human peripheral blood mononuclear cells exposed to UFPM, BC, and PS-NPs under similar experimental conditions. Oxidative stress, mitochondrial adaptation, respiratory chain integrity, mitochondrial integrated stress response, inflammatory signaling, and systems-level interactions between molecules were analyzed through the evaluation of the expression of NRF2, HIF-1α, PGC-1α, TFAM, OMA1, DELE1, mitochondrial ND1, Complex I-V, NF-κB, TNF-α, and NLRP3, and the use of principal component analysis, hierarchical clustering, and correlation networks. Results All three nanoparticle exposures elicited oxidative stress and mitochondrial stress-related responses with distinct kinetics and mechanisms. UFPM mostly induced an acute antioxidant response and mitochondrial adaptation; BC led to sustained mitochondrial dysfunction and sustained induction of OMA1 and DELE1 transcripts, consistent with an OMA1-DELE1 associated mitochondrial stress response and inflammation; while PS-NPs induced low but sustained mitochondrial adaptation, along with mitochondrial biogenesis and stress responses. Based on the systems-level analysis, oxidative stress, mitochondrial adaptation, mitochondrial ISR, and inflammation appear to be highly correlated molecular pathways independent of the physicochemical properties of nanoparticles, while the coordinated expression of OMA1 and DELE1 was linked with mitochondrial stress response and inflammation, and the OMA1-DELE1 pathway might be considered as a possible regulatory module for future validation. Discussion Overall, we found that activation of the mitochondrial stress response is a common pathway underlying the cytotoxic effects of different chemical nanoparticles. The results of the present study provide new understanding of the molecular pathways responsible for the immunotoxic effects of nanoparticles and identify OMA1, DELE1, NRF2, PGC-1α, TFAM, ND1, and Complex I-V as possible biomarkers.