Protein disulfide isomerase PDI-6 regulates Wnt secretion to coordinate inter-tissue UPR mt activation and lifespan extension in C. elegans.

Coordination of inter-tissue stress signaling is essential for organismal fitness. Neuronal mitochondrial perturbations activate the mitochondrial unfolded-protein response (UPRmt ) in the intestine via the mitokine Wnt signaling in Caenorhabditis elegans. Here, we found that the protein disulfide isomerase PDI-6 coordinates inter-tissue UPRmt signaling via regulating the Wnt ligand EGL-20. PDI-6 is expressed in the endoplasmic reticulum (ER) and interacts with EGL-20 through disulfide bonds that are essential for EGL-20 stability and secretion. pdi-6 deficiency results in misfolded EGL-20, which leads to its degradation via ER-associated protein degradation (ERAD) machinery. Expression of PDI-6 declines drastically with aging, and animals with pdi-6 deficiency have decreased lifespan. Overexpression of PDI-6 is sufficient to maintain Wnt/EGL-20 protein levels during aging, activating the UPRmt , and significantly extending lifespan in a Wnt- and UPRmt -dependent manner. Our study reveals that protein disulfide isomerase facilitates Wnt secretion to coordinate the inter-tissue UPRmt signaling and organismal aging.