By Dr. Chinta Sidharthan Reviewed by Danielle Ellis, B.Sc. Aug 12 2024
In a recent study published in Science Advances, researchers from the University of California, Berkeley, used the nematode model Caenorhabditis elegans to determine whether the olfactory nervous system could non-autonomously control the mitochondrial unfolded protein response in response to cellular stress. Study: Olfaction regulates peripheral mitophagy and mitochondrial function. Image Credit: Lightspring/Shutterstock.com Background
A critical part of maintaining a state of cellular homeostasis is coordinating responses to environmental stress across tissues. Substantial evidence now supports the fact that the central nervous system regulates stress across all tissues. Furthermore, cell non-autonomous induction of stress responses occurs in peripheral tissues when unfolded protein responses (UPR) in the mitochondria and the endoplasmic reticulum are activated in the neurons.
Stressed cells undergo misfolding or unfolding of proteins, and UPR transmits protein folding status information to the nucleus to enable cellular stress responses or induce apoptotic cell death. The non-autonomous control of cellular stress responses is believed to be essential for the organism to survive toxic environmental conditions.
The olfactory system is thought to play a vital role in the non-autonomous regulation of homeostasis and longevity. Studies in murine models have shown that olfactory signals can control metabolic regulation, while research on C. elegans shows that the olfactory nervous system plays a central role in assessing environmental signals and initiating cellular responses. About the study
In the present study, the researchers conducted experiments with C. elegans in which they manipulated the AWC neurons to observe the non-autonomous control of mitochondrial UPR. The AWC neurons stand for amphid wing ‘C’, and are the primary olfactory neurons in nematodes or roundworms involved in chemotaxis responses to volatile compounds. They are found in amphids, which are the nematode's principal olfactory sensory organs located in the cuticle folds in the head.
Although C. elegans are bacterivores, their tissues must also be defended against food-borne bacterial pathogens such as Pseudomonas aeruginosa. Furthermore, the tissues must be able to tolerate and eliminate toxic metabolites such as reactive oxygen species generated by the mitochondria.
Studies have shown that during P. aeruginosa infection, C. elegans activate the stress-activated transcription factor atfs-1 of mitochondrial UPR to induce the genes involved in innate immune responses and to tackle mitochondrial damage. However, in the natural environment, C. elegans are exposed to a potpourri of pathogenic and commensal bacteria, and they use bacterial metabolites to distinguish the harmful bacteria from the beneficial ones.
Olfactory neurons are the primary mode of detecting volatile metabolites produced by bacteria, which led the researchers to assume that the coordination of mitochondrial UPR induction must occur mainly through olfactory neurons.
Therefore, they conducted experiments where the AWC neuron pair was either silenced or ablated to understand the role of these neurons in mitochondrial UPR and stress responses. Various parameters, such as mitochondrial oxygen consumption rates and mitochondrial membrane potentials, were compared between the C. elegans with ablated AWC neurons and those that did not undergo AWC ablation. Related StoriesResearch highlights importance of dietary education to combat rising childhood obesity ratesFirst international consensus unifies fasting terminology to boost global researchResearch highlights green tea's potential role in improving ovarian cancer outcomes
The impact of exposures to various odorants, including volatile bacterial metabolites such as 2-butanone and 2,3-pentanedione, as well as pharmacological treatments such as serotonin on animals with manipulated AWC neurons, was also examined. The role of serotonin signaling in the regulation of mitochondrial homeostasis was evaluated using human fibroblast cell cultures. Results
The study found that the AWC olfactory neurons in C. elegans play a central role in the regulation of peripheral mitochondrial dynamics. The animals with silenced AWC neurons exhibited mitochondrial UPR induction and lower levels of mitochondrial oxidative phosphorylation. Furthermore, these animals also experienced a depletion of the mitochondrial deoxyribonucleic acid (mtDNA), indicating mitophagy.
The ablation of AWC olfactory neurons triggered mitochondrial UPR and increased the resistance to the pathogenic bacteria P. aeruginosa through the activation of atfs-1. Serotonin pathways were found to be the principal mediators of stress responses involving mitochondrial function, as mutations impacting serotonin production suppressed these responses, and exogenous serotonin was able to replicate those responses in C. elegans and human fibroblast cells.
The researchers also found that olfactory sensing of 2,3-pentanedione, the volatile bacterial metabolite, could also non-autonomously regulate the peripheral dynamics of the mitochondria, which was not observed in the neuronal perturbations of the mitochondria that occurred due to genetic factors involving serotonin pathways.
These findings suggested that the olfactory nervous system might be involved in conveying volatile metabolite cues from bacteria such as 2,3-pentanedione, which might then be preparing the peripheral tissues for disturbances in homeostasis such as pathogenic bacterial infections or metabolic stress. Conclusions
Overall, the study found that the olfactory neurons play an important role in regulating the mitochondrial dynamics in C. elegans in preparation or response to pathogenic infections or metabolic stress that might cause homeostatic disturbances. While the results have described a potential model through which olfactory signals regulate mitochondrial stress responses and function, as well as mitochondrial quality control, the mechanistic regulation of processes such as mitophagy needs to be explored further.Journal reference: Dishart, J. G., Pender, C. L., Shen, K., Zhang, H., Ly, M., Webb, M. B., & Dillin, A. (n.d.). 2024. Olfaction regulates peripheral mitophagy and mitochondrial function. Science Advances, 10(25), eadn0014. DOI:10.1126/sciadv.adn0014, https://www.science.org/doi/10.1126/sciadv.adn0014
