Copper overload induces lifespan shortening through activating mitochondrial respiration in Caenorhabditis elegans

Despite being a common environmental heavy metal, copper is an essential trace element for organisms, playing a vital role in the assembly and function of the mitochondrial respiratory chain. However, excessive copper exposure induces significant biological toxicity. Copper overload can lead to mitochondrial dysfunction, growth inhibition, and cytotoxicity, but its impact on lifespan and the underlying mechanism remains largely unexplored. Caenorhabditis elegans, characterized by a short life cycle, transparency, and high genetic homology (60-80 %) with humans, serves as an ideal model for researching the homeostasis and toxicity of metal ions. In this study, we utilized CuCl₂ in combination with elesclomol in C. elegans to establish a copper overload model and observed an increase in copper ion concentrations within the nematodes, inducing a series of mitochondrial structural and functional damages. Previous studies have confirmed that mitochondrial respiration not only constitutes the physiological basis for the occurrence of copper overload but also represents a key biological process regulating the lifespan of nematodes. Accordingly, we found that copper overload shortened nematode lifespan and reduced infection resistance by activating mitochondrial respiration, which decreased ROS levels and downregulated lifespan-related genes aak-2 and hif-1. In conclusion, these findings demonstrated the lifespan-shortening effect of copper overload on C. elegans, and revealed its pathological mechanism, thereby identifying potential therapeutic targets for aging-related diseases.