Cuproptosis inducers mediate cold lethality via SLCR-46.1 in C. elegans

Cuproptosis denotes cell death triggered by copper accumulation. However, its role in natural environmental responses remains unclear. Here, we demonstrate that cuproptosis contributes to cold-induced lethality in C. elegans. A mutant for the lysosomal copper transporter gene slcr-46.1 exhibited defective cold tolerance due to copper accumulation in the pharyngeal muscle upon cold exposure. The abnormal cold tolerance of the slcr-46.1 mutant was suppressed by interference with copper homeostasis and cuproptosis-signaling genes. Chelating copper ions in the slcr-46.1 mutant rescued the abnormal cold tolerance, while inhibiting cuproptosis signaling in wild-type worms inhibited cold-induced lethality. In addition, the cold lethality in the slcr-46.1 mutant was not caused by activation of the oxidative stress pathway observed in ferroptosis (iron-dependent cell death). Here, we show evidence that cuproptosis plays a critical role in cold-induced lethality in an animal. This study reveals that copper-dependent cell death (cuproptosis) drives cold-induced death in nematodes through copper accumulation, and further indicates that low temperature may activate related cuproptosis pathways in mammalian cells.