GPCR signaling coordinates inter-tissue mitochondrial stress communication in C. elegans

The nervous system is essential for coordinating the body’s response to stress. Neurons under mitochondrial stress could release signals and communicate with peripheral tissues to activate the body-wide mitochondrial unfolded protein response (UPR^mt) for physical adaptation.

G-protein-coupled receptors (GPCRs) play an important role in transmitting various extracellular signals in cells and have been considered one of the largest families of validated drug targets. However, whether GPCR signaling is required to coordinate inter-tissue mitochondrial stress communication remains largely unknown.

Dr. Tian Ye’s group from the Institute of Genetics and Developmental Biology of the Chinese Academy of Sciences (CAS) revealed that GPCR signaling is essential to coordinate intestinal UPR^mt activation in response to neuronal mitochondrial disturbances in Caenorhabditis elegans.

In this study, researchers identified that an SRZ-75 GPCR is expressed in a pair of ADL neurons (amphid neurons with two ciliated sensory terminals) and mediates neuronal-to-gut UPR.^mt Communication. SRZ-75 couples with its downstream Gαq signaling to promote the release of neuropeptides from ADL neurons to propagate nonautonomous mitochondrial stress activation of the cell.

According to the researchers, the ablation of ADL neurons strongly attenuated the intestinal UPR^mt activation in response to mitochondrial neuronal stresses. Enhanced GPCR/SRZ-75-Gαq signaling in ADL neurons induced intestinal UPR^mt activation and subsequent enhancement of host resistance to Pseudomonas aeruginosa (PA14).

Furthermore, enhanced ADL-GPCR SRZ-75-Gαq signaling also enhanced proteostasis, altered mitochondrial morphology, and altered lipid metabolism in peripheral tissues.

In summary, this work provides mechanistic insights into neuronal GPCR signaling coordinating the systemic response to mitochondrial stress. More importantly, activation of GPCR and downstream signaling in just two ADL neurons altered a variety of distinct physiological characteristics in distal tissues, including altered metabolic status, enhanced proteostasis, and increased stress resistance.

This cover study titled “Two sensory neurons coordinate the systemic response to mitochondrial stress via GPCR signaling in C. elegans” was published online in Development cell October 28.