Neuropeptide signaling regulates mitochondrial UPR activity and extended lifespan resulting from methionine restriction.

Abstract

Mild disruptions to mitochondrial function can lead to the activation of an adaptive program that extends animal lifespan. The mitochondrial unfolded protein response (UPRmt) is associated with such conditions that prolong lifespan. We previously discovered that methionine restriction, resulting from the genetic loss of methionine synthase in C. elegans, activated the UPRmt and extended lifespan. Here, we demonstrate that methionine restriction activates the UPRmt and delays aging within the intestine of C. elegans. Using a forward genetics approach, we identified a role for PKC-1, the C. elegans ortholog of protein kinase C epsilon/eta (PKC???), in regulating methionine restriction-associated UPRmt (MetR-UPRmt). PKC-1 activity was required for the increased lifespan and host resistance during infection that was associated with methionine restriction. Strikingly, PKC-1 was not required for UPRmt activation resulting from dysfunctional oxidative phosphorylation, mitochondrial protein translation, or mitochondrial protein import. We find that secretion of neuropeptides from dense-core vesicles is required for MetR-UPRmt activity, consistent with the role of PKC-1 in regulating this form of neurotransmission. We also identify specific neuropeptides (INS-27, INS-34, and INS-35) that positively regulate MetR-UPRmt activity and associated lifespan extension. Mechanistically, we find that neuropeptide signaling regulates MetR-UPRmt activity in part by altering mitochondrial network dynamics. Together, our data suggest a model in which neuropeptide signaling preferentially regulates UPRmt activity and lifespan extension induced by intestinal methionine restriction, but not by other forms of mitochondrial dysfunction.