Neurons and filamentous fungi are highly polarized cells that share features such as long-distance vesicle transport. Here, we identify another intriguing similarity: the function of seven-transmembrane G-protein coupled receptors (GPCRs) in energy metabolism regulation. In mouse neurons, the cannabinoid receptor 1 (CB1) and GprC, a C. elegans pheromone ascaroside-sensing receptor of the nematode-trapping fungus Arthrobotrys flagrans, both localize to the cytoplasmic membrane and to mitochondria. In the fungus, nematode signaling stimulates respiration, preparing it for the battle with C. elegans, whereas the CB1 receptor in neurons decreases respiration.

GPCRs are a large class of eukaryotic receptor proteins and are key drug targets. Typically located at the cell surface, they perceive signals and initiate downstream processes. However, their localization and function at mitochondria or other cellular sites is poorly understood.

Nematode-trapping fungi are soil-borne microorganisms that switch from a saprotrophic to a predatory lifestyle when nutrients are scarce and nematodes are present. Nematodes release ascaroside pheromones, which the fungi “smell”. Ascarosides are very important signaling molecules for nematodes themself, and therefore the evolutionary pressure of the predator did not favor counter-selection. The ascaroside-sensing GPCRs in C. elegans show only weak sequence similarity to the fungal receptor, suggesting convergent evolution. Interestingly, one of the C. elegans receptors is also predicted to localize to mitochondria. In many other fungi one or two GPCRs with putative mitochondrial localization were predicted suggesting broad evolutionary conservation of GPCR functions in mitochondria. You can learn more about nematode-trapping fungi here: https://www.iab.kit.edu/microbio/1085.php

 The discovery of the dual localization and function of GPCRs in A. flagrans opens new avenues for understanding the cell biological pathways and molecular mechanisms of action at or in mitochondria.

Figure: Left, collage of the localization of GprC in A. flagrans. At the tip of hyphae, it localizes to mitochondria (green, GprC-GFP; red, mitochondrial staining with mitotracker; yellow, overlay). In hyphae away from the tip, the receptor localizes to the cell membrane (red, mitochondria; green GprC-GFP). The blue structures are a fungal trap. A model of the receptor-ligand binding site is shown in the center. Right, scheme illustrating dual localization and function of GprC in a fungal cell.