Mitochondria affect antibacterial immunity in cross talk with innate immune response molecules coded by genes of...

Mitochondria are dynamic, semi-autonomous organelles that, in addition to their central role in ATP production, regulate calcium homeostasis, iron metabolism, apoptosis, and innate immune signalling. Although the mitochondrial genome encodes only 37 genes, mitochondrial architecture, bioenergetic function, and dynamics are governed predominantly by nuclear-encoded proteins, necessitating highly coordinated communication between mitochondrial DNA (mtDNA) and the nuclear genome. Disruption of this bidirectional mitochondrial-nuclear crosstalk has been increasingly implicated in the pathogenesis of numerous diseases across species; however, the molecular mechanisms underlying this communication remain incompletely understood.

In the present study, we used Anas platyrhynchos as a model of duck pasteurellosis to investigate mitochondrial-nuclear interactions in the regulation of innate immune responses during Pasteurella multocida infection. We characterized the mitochondrial (cytochrome b and cytochrome c) and nuclear genes (NLRP3, IL-18, and STING) of duck, in silico molecular docking, PHYRE 2 for PDB structure prediction, pymol visualization, and experimental validation with differential mRNA expression profiling.

Our findings demonstrate that the mitochondrially encoded proteins cytochrome b and cytochrome c functionally interact with the nuclear-encoded immune regulators NLRP3, IL-18, and STING through the NOD-like receptor signalling pathway, phagocytic pathways, and the cytosolic DNA-sensing pathway. Furthermore, molecular docking analyses identified putative interaction sites between IL-18 and P. multocida, providing additional support for the functional relevance of these immune pathways during bacterial infection. To our knowledge, this study provides the first evidence in an animal model that mitochondrial retrograde signalling influences the regulation of nuclear immune genes during bacterial infection. These findings reveal a previously unrecognized mechanism through which mitochondrial gene products modulate host innate immune responses, thereby advancing our understanding of mitochondrial-nuclear communication in host-pathogen interactions.