Overloaded mitochondrial stress drives reproductive damage in GC-1 mouse spermatogonia cells exposed to nickel nanoparticle.

Abstract

Nickel nanoparticles (Ni NPs) are widely used in industrial and commercial sectors, raising concerns about their potential occupational and environmental toxicity. Male infertility has increased significantly in recent decades, with environmental exposures playing a recognized role. Ni NPs have been identified as toxic agents that induce testicular damage and sperm abnormalities, yet their underlying molecular mechanisms are unknown. In this study, mouse spermatogonia GC-1 cells were used as an in vitro model to explore the role of mitochondrial autophagy (mitophagy) in the induced apoptosis of Ni NPs. Ni NPs significantly reduced cell viability, increased intracellular ROS levels, disrupted mitochondrial membrane potential, and triggered germ cell apoptosis. PINK1 and Parkin, key mitophagy-related proteins, exhibited significant upregulation. Cyclosporin A was used to inhibit mitophagy, attenuating mitochondrial damage and reducing apoptosis. In addition, PINK1 knockdown achieved by lentiviral transfection confirmed its critical role in mediating Ni NPs-induced mitophagy and subsequent cell death. These findings demonstrate that overactivation of the PINK1/Parkin pathway promotes apoptosis to Ni NPs exposure by mitophagy. Our study provides new mechanistic insights into the role of mitophagy in reproductive damage caused by nanomaterials.