Beyond the nucleus, no other organelle in eukaryotic cells captures the public’s imagination quite like mitochondria: They are the engines of cellular energy production; they possess their own DNA, and they are passed from generation to generation from mothers to offspring.
Now scientists have revealed that these bean-shaped energy factories, known for the production of ATP, the key fuel of life, also play an extraordinary role in harnessing the immune response during infection—these organelles are critical in mediating a powerful antibacterial defense.
The discovery by investigators at Australia’s University of Queensland, who worked with collaborators in Switzerland and Spain, demonstrates an unexpected role for these crucial constituents of cells. The team showed that mitochondrial fission underlies an immune response, producing antibacterial capability in a host of organisms from the lowly worm to complex mammals. Results of the research are published in Science Immunology.
Fission is key to fighting invaders
“Our findings suggest that mitochondrial fission is an evolutionarily conserved pathway that provides cell-autonomous control of infection and can be targeted to combat antibiotic-resistant bacterial pathogens,” Ronan Kapetanovic and colleagues write in the journal.
Mitochondrial division—or fission—can promote antibacterial defense pathways in mammalian macrophages and worms, according to the study, which identified the regulatory mechanisms that control these defense pathways. Findings from the research could inform future therapeutic targets while highlighting unique mitochondrial functions in the fight against infection.
Going into their study, the University of Queensland team knew that earlier research had shown that microbial signals and stress can induce mitochondrial changes, but it had remained unclear whether mitochondrial fission can enhance host immune defenses.
Kapetanovic and colleagues showed that E. coli infections triggered mitochondrial fission in cultured mouse and human macrophages as well as in the worm, Caenorhabditis elegans, which then boosted bacterial clearance.
Additional experiments by the team of investigators revealed that mitochondrial fission triggered the formation of antimicrobial lipid droplets and activated a stress pathway called the mitochondrial unfolded protein response, UPRmt.
The UPRmt prompted the nuclear translocation of transcription factor ATF5, driving the expression of antimicrobial effector genes. However, the researchers also determined that ATF5 inhibited the production of fission-mediated lipid droplets, curtailing excessive defense responses. The UPRmt, the team found, aids restoration of cellular homeostasis.
Fission creates more mitochondria
As a first step in their experiments, scientists infected mouse macrophages with E. coli and found that the number of mitochondria increased, a direct result of fission. The fission, in this instance, was induced in response to E. coli infection.
Then, with the help of a cocktail of compounds and the silencing of a gene involved in fission, scientists wanted to see what would happen if the organelles were directed toward mitochondrial fusion—the opposite pathway of fission. The result was increased intracellular E. coli in the macrophages.
Still, the lesson learned from E. coli was not universal, and there apparently are significant differences in mitochondrial immune reactions from one pathogen to another. With Salmonella typhimurium, for example, researchers found that the pathogen survives inside macrophages and orchestrates mitochondrial behavior to the benefit of the bacteria, preventing mitochondrial fission and the substantial increase in additional mitochondria.
But Kapetanovic and colleagues had an answer to the craftiness of Salmonella typhimurium: Inhibiting the enzyme HDAC6 promoted mitochondrial fission and lipid droplet formation, enhancing bacterial clearance—and suggesting that HDAC6 could be a therapeutic target to control otherwise recalcitrant infections.
In an editorial commentary, Claire Olingy, a senior editor at Science Immunology, writes that mitochondria are central signaling and metabolic hubs “whose function is dynamically regulated by the processes of fusion and fission.”
“Kapetanovic and colleagues found that mitochondrial fission enhances bacterial clearance in macrophages and Caenorhabditis elegans,” Olingy continued, noting that “bacterial infection triggered mitochondrial fission, activating the mitochondrial unfolded protein response and production of antimicrobial lipid droplets.”
“These findings,” Olingy added, “identify a conserved, targetable axis linking mitochondrial dynamics to innate immune defense.”