In Vivo Effects of Silver Nanoparticles on Development, Behavior, and Mitochondrial Function are Altered by Genetic Defects in Mitochondrial Dynamics

Abstract

Silver nanoparticles (AgNPs) are extensively used in consumer products and biomedical applications, thus guaranteeing both environmental and human exposures. Despite extensive research addressing AgNP safety, there are still major knowledge gaps regarding AgNP toxicity mechanisms, particularly in whole organisms. Mitochondrial dysfunction is frequently described as an important cytotoxicity mechanism for AgNPs; however, it is still unclear if mitochondria are the direct targets of AgNPs. To test this, we exposed the nematodeCaenorhabditis elegans to sublethal concentrations of AgNPs and assessed specific mitochondrial parameters as well as organismal-level endpoints that are highly reliant on mitochondrial function, such as development and chemotaxis behavior. All AgNPs tested significantly delayed nematode development, disrupted mitochondrial bioenergetics, and blocked chemotaxis. However, silver was not preferentially accumulated in mitochondria, indicating that these effects are likely not due to direct mitochondria–AgNP interactions. Mutant nematodes with deficiencies in mitochondrial dynamics displayed both greater and decreased susceptibility to AgNPs compared to wild-type nematodes, which was dependent on the assay and AgNP type. Our study suggests that AgNPs indirectly promote mitochondrial dysfunction, leading to adverse outcomes at the organismal level, and reveals a role of gene–environment interactions in the susceptibility to AgNPs. Finally, we propose a novel hypothetical adverse outcome pathway for AgNP effects to guide future research.

Surface Defects Regulate the in Vivo Bioenergetic Response of Earthworm Eisenia fetida Coelomocytes to Molybdenum Disulfide Nanosheets

“…The levels of ATP and ADP metabolism, key metabolites shared by OXPHOS, glycolysis, and the TCA cycle, did not change significantly in all tested groups (Figures S13E,L). ATP and ADP were measured based on steady-state levels, rather than ADP phosphorylation . However, the compensatory mechanism of mitochondrial respiration may allow for regulating ATP production and use by bypassing the inhibition of OXPHOS .…”

“…ATP and ADP were measured based on steady-state levels, rather than ADP phosphorylation. 68 However, the compensatory mechanism of mitochondrial respiration may allow for regulating ATP production and use by bypassing the inhibition of OXPHOS. 67 Although the OXPHOS intermediates NADH, NADPH, and fumarate were below the detection limits, the results of Mito-RETC complex activity (Figures 2D−H) provide evidence that OXPHOS was strongly affected by DR-MoS 2 .…”

Rotenone Modulates Caenorhabditis elegans Immunometabolism and Pathogen Susceptibility

“…Indeed, chemicals may impact chemosensory behavior controlling the C. elegans ability to be attracted or avoid certain natural products. For example, we have recently shown that a sublethal dose of silver nanoparticles can completely block the C. elegans ability to be attracted to a food-like odor ( 80 ). Contributing to this idea is the fact that rotenone is also well known for causing neurotoxic effects ( 81 ).…”

Heterozygous p.Y955C mutation in DNA polymerase γ leads to alterations in bioenergetics, complex I subunit expression, and mtDNA replication

“…Human mitochondrial dysfunction is further complicated by evidence that genetic mutations can enhance mitochondrial toxicity suggesting there are unidentified environmental and pharmacological stressors that cause mitochondrial toxicity in individuals harboring mutant alleles. For example, a recent report using the nematode Caenorhabditis elegans showed that the sublethal concentrations of silver nanoparticles, which are extensively used in consumer products and biomedical applications, alter the development, behavior, and mitochondrial function in worms that harbor genetic defects in mitochondrial dynamics ( 87 ). Furthermore, a recent study demonstrated that exposure to ddC induces mtDNA stress leading to activation of the STING1/TMEM173-mediated DNA sensing pathway and autophagy-dependent ferroptotic cell death ( 88 ).…”