Mitochondrial Fission Can Boost Antimicrobial Defenses

Just as pathogens deploy a range of infection strategies, multicellular organisms are equipped with biological defenses to counter them. These involve a cascade of responses, with mitochondria playing a central role in the immune reaction.

Previous studies have shown that stress and microbial infections can trigger mitochondrial adaptations, such as the mitochondrial unfolded protein response (UPR^mt), which helps restore cellular homeostasis, and mitochondrial fission. However, whether these changes directly strengthen host defense remained unclear. To address this, researchers from the University of Queensland and their collaborators explored the connection between mitochondrial fission and immune function.

In their findings, recently published in Science Immunology, the team demonstrated that an Escherichia coli infection induced mitochondrial fission, which in turn activated UPR^mt and stimulated the production of antimicrobial lipid droplets.¹ These responses improved bacterial clearance in both mammalian macrophages and Caenorhabditis elegans. The researchers also identified a specific transcription factor and enzyme that regulate this antimicrobial pathway, highlighting their potential as therapeutic targets.

The researchers first infected mouse macrophages with E. coli and found that an increase in mitochondria, due to mitochondrial fission, occurred in response to the infection. To confirm this observation, the team then used a co-treatment of compounds to push the mitochondria in the opposite direction—toward mitochondrial fusion. To do so, they used mitochondrial fusion promoter M1 together with mitochondrial division inhibitor one, or by silencing a gene involved in fission; neither component affected bacterial growth, but the researchers observed increased intracellular E. coli in the macrophages.

These findings showed that mitochondrial fission helped macrophages eliminate bacteria essentially by “dividing and conquering.” The researchers observed a similar pattern in C. elegans, where organisms with more mitochondrial fission had lower levels of bacteria.

Next, the researchers homed in on the activity of the UPR^mt during an infection in the worms. Under stress conditions, the UPR^mt process begins with nuclear translocation of the activating transcription factor associated with stress-1 (ATFS-1) to restore mitochondrial homeostasis. Using a green fluorescent protein (GFP) marker, the team observed higher GFP signals—indicating stronger UPR^mt activity—in worms with elevated mitochondrial fission. This showed that mitochondrial splitting activates this protective pathway.

They then tested whether a similar mechanism exists in mammalian cells by examining atf4 and atf5, which are related to atfs-1. When these genes were silenced, the macrophages had higher levels of intracellular E. coli, suggesting these factors are important for fighting infection.

To dig deeper, the researchers examined ATF5 in mammalian cells and the antimicrobial responses it controls. They found that it activated genes involved in producing antimicrobial lipid droplets (LDs), and consistent with this, they observed an increase in LD density in the cells skewed toward fission.

However, not all pathogens behave the same way. Some, like Salmonella typhimurium, can survive within macrophages and manipulate mitochondrial behavior to their advantage. In this case, S. typhimurium can inhibit mitochondrial fission.

To determine a way to combat this mechanism, the team investigated histone deacetylase 6 (HDAC6), an enzyme involved in mitochondrial fusion initiation. When the researchers inhibited HDAC6 in cells infected with S. typhimurium, mitochondrial fission and LD formation increased, improving the cells’ ability to clear the bacteria.

Overall, these findings provide a deeper understanding of mitochondrial adaptations and suggest that HDAC6 could be a therapeutic target to control infections.