ABOVE: Researchers found that Caenorhabditis elegans’ olfactory neurons can prepare the organism against pathogens through regulation of the mitochondria. ©iStock, HeitiPaves
Just like humans, Caenorhabditis elegans worms encounter gut-attacking bacterial pathogens through their diet. To thrive in their new hosts, bacteria seek out iron. To protect their iron supplies, which are stored in mitochondria, the worms activate a defense tactic. How the worms detect these environmental threats and trigger a mitochondrial response intrigued scientists, including Andrew Dillin, a molecular and cell biologist at the University of California, Berkeley.
Because C. elegans use their sense of smell to detect food as they wiggle around, Dillin remarked, “We started thinking that maybe what the nervous system is doing is picking up on the pathogen. What better way to do it than to smell the pathogen?”
In a paper in Science Advances, Dillin and his team showed that C. elegans worms’ sense of smell coordinates a mitochondrial response, particularly in intestinal cells, to resist bacterial infection.1 The researchers speculate that this process is conserved in mammals for pathogen detection and immune regulation.
The researchers focused their investigation on a pair of olfactory neurons called amphid wing "C" (AWC), which serve as a scent detection system by activating in the absence of odor and turning off when odors are present. Researchers previously found that ablating these neurons boosted pathogen resistance and improved worm survival.2 However, it was unclear how this might be connected to the mitochondrial stress response.
To solve this worm mystery, Dillin and his team silenced AWC neurons using two approaches: one involved genetic tools followed by exposure to Pseudomonas aeruginosa, while the other involved a natural method using P. aeruginosa’s metabolite 2,3-pentanedione.
Not only did these worms show resistance to infection, but they also exhibited an increase in activity of a transcription factor that typically shows up during the mitochondrial unfolded protein response (UPRMT), a process triggered when mitochondria are overwhelmed with an onslaught of misfolded proteins. This led to changes indicative of protective efforts: reduced oxidative phosphorylation, oxygen consumption rates, and mitochondrial DNA (mtDNA) levels.
The researchers used a cationic dye to stain for active mitochondria at the site of infection in the intestines. Under the microscope, they found that the pathogen triggered mitochondrial responses throughout the bodies of AWC-silenced worms. These worms had a reduced intensity of stain, indicating fewer mitochondria, which correlated with lower activity and mtDNA levels. These findings suggest that smelling a pathogen prepares the worm’s gut against infection.
Read Pukkila-Worley, an infectious disease physician at the University of Massachusetts Chan Medical School who was not involved in the study, explores mechanisms of immune homeostasis in intestinal epithelial cells. He said, “This paper makes a lot of evolutionary sense, where olfactory neurons are poised to sample the environment and to prime the host to handle challenges from either stress or pathogens.”
Since the smell of pathogens puts worms on high alert, Dillin wanted to identify the signaling molecule that sounded the mitochondrial alarm. Dillin’s team homed in on serotonin, which has previously been established as a mitochondrial signaling molecule.3 The researchers tested whether loss of tryptophan hydrolase 1, the gene required for serotonin synthesis, was required for AWC-mediated UPRMT induction. The absence of serotonin signaling inhibited the mitochondrial stress response, but exogenous serotonin supplementation activated UPRMT, showing that mitochondrial changes rely on serotonin signaling.
Dillin wondered whether the loss of AWC affected mitophagy, another maintenance pathway that removes damaged or excess mitochondria, and if the observed reduction in oxygen consumption and mtDNA was a consequence of mitochondrial clearance. Mutant worms lacking a key mitophagy gene were more sensitive to P. aeruginosa infection. When Dillin and his team delved into the mechanisms underlying this effect, they found that the mitophagy gene is required for the reduction in oxygen consumption and mtDNA observed in AWC-ablated worms.
“And [this olfactory response] actually does even more than protect mitochondria. It [caused mitophagy], splitting the mitochondria up into smaller units, so there's less opportunities for the pathogen and it can't find all the mitochondria,” said Dillin. Although mitophagy seems to be an anticipatory strategy to resist pathogenic insult, Dillin noted that there is still much to learn about this process.
Dillin and his team plan to continue teasing apart the nuances underlying the neural circuits that link olfactory neurons to peripheral cells, such as the gut, and neurotransmitters that confer resistance to pathogen infection. He hopes to find a similar result in mice and, more broadly, in mammals.
- Dishart JG, et al. Olfaction regulates peripheral mitophagy and mitochondrial function. Sci Adv. 2024;10(25):eadn0014.
- Venkatesh SR, et al. Amphid sensory neurons of Caenorhabditis elegans orchestrate its survival from infection with broad classes of pathogens. Life Sci Alliance. 2023;6(8):e202301949.
- Zhang Q, et al. The mitochondrial unfolded protein response is mediated cell-non-autonomously by retromer-dependent Wnt signaling. Cell. 2018;174(4):870-883.e17.