Systemic mitochondrial disruption is a key event in the toxicity of bacterial pore‐forming toxins to Caenorhabditis elegans

Abstract

Pore-forming toxins (PFTs) are important weapons of multiple bacterial pathogens to establish their infections. PFTs generally form pores in the plasma membrane of target cells; however, the intracellular pathogenic processes triggered after pore-formation remain poorly understood. Using Caenorhabditis elegans as a model and Bacillus thuringiensis nematicidal Cry PFTs, we show here that the localized PFT attack causes a systemic mitochondrial damage, important for the PFT toxicity. We find that PFTs punch pores only in gut cells of nematodes, but unexpectedly mitochondrial disruption is able to occur in distal unperforated regions, such as the head and muscle tissues. We demonstrate that PFTs affect the activity of the mitochondrial respiratory chain (MRC) complex I resulting in the loss of mitochondrial membrane potential (ΔΨ m ), which causes further mitochondrial fragmentation and the reduction of total mitochondrial content. Worms with decreased ΔΨ m or inhibited MRC activity show higher sensitivity to PFTs. The inhibition of mitochondrial fission or the increase of mitochondrial content markedly improves the survival of animals treated with PFTs. These findings suggest that mitochondrial changes underpin PFT-mediated toxicity against nematodes and that systemic mitochondrial disruption caused by localized pore-formation represents a conserved key intracellular event in the mode of action of PFTs.

Biosynthesis of Cry5B-Loaded Sulfur Nanoparticles using Arthrobotrys oligospora Filtrate: Effects on Nematicidal Activity, Thermal Stability, and Pathogenicity against Caenorhabditis elegans

“…In addition, the fluorescence intensity was observed throughout the entire body of C. elegans (Figure b), not only in the digestive tract as previously reported . Different durations of Cry5B exposure may have contributed to the inconsistent results.…”

“…In addition, the fluorescence intensity was observed throughout the entire body of C. elegans (Figure 4b), not only in the digestive tract as previously reported. 46 Different durations of Cry5B exposure may have contributed to the inconsistent results. This study incubated C. elegans with Cry5B protein for 5 days, the same condition as the nematicidal assay, prior to PI staining, whereas a previous study incubated C. elegans with Cry5B protein for 7 h prior to PI staining.…”

Insights into the antimicrobial effects of ceritinib against Staphylococcus aureus in vitro and in vivo by cell membrane disruption

“…It was universally acknowledged that oxidative damage, especially ROS, has a destructive effect on the function of proteins, played a prominent role in metabolic disturbance, and may even result in bacterial death (Ezraty et al 2017 ). Hence, we measured the ROS level by using the indicator H2DCFDA (Shi et al 2021 ) and found that CERI could significantly elevate the ROS level in bacteria at a concentration of 8 μg/mL (Additional file 3 : Fig. S2G).…”

C. elegans monitor energy status via the AMPK pathway to trigger innate immune responses against bacterial pathogens

“…Mitochondria are constantly fusing and dividing, which is essential for maintaining mitochondrial respiration and homeostasis, even in cell death 36,37 . It has been proven that pore-forming toxins (PFTs) from pathogens can cause serious mitochondrial disruption in C. elegans 17,18,38 . The mitochondria fragmentation (MF) phenomenon can lead to bioenergetics defects, resulting in an imbalance of cell energy 39 .…”