Antimicrobial mitochondrial reactive oxygen species induction by lung epithelial immunometabolic modulation

Authors

Yongxing Wang
Vikram V Kulkarni
Jezreel Pantaleón García
Miguel M Leiva-Juárez
David L Goldblatt
Fahad Gulraiz
Lisandra Vila Ellis
Jichao Chen
Michael K Longmire
Sri Ramya Donepudi
Philip L Lorenzi
Hao Wang
Lee-Jun Wong
Michael J Tuvim
Scott E Evans

Publication Date

9-1-2023

Journal

PLoS Pathogens

Abstract

Pneumonia is a worldwide threat, making discovery of novel means to combat lower respiratory tract infection an urgent need. Manipulating the lungs' intrinsic host defenses by therapeutic delivery of certain pathogen-associated molecular patterns protects mice against pneumonia in a reactive oxygen species (ROS)-dependent manner. Here we show that antimicrobial ROS are induced from lung epithelial cells by interactions of CpG oligodeoxynucleotides (ODN) with mitochondrial voltage-dependent anion channel 1 (VDAC1). The ODN-VDAC1 interaction alters cellular ATP/ADP/AMP localization, increases delivery of electrons to the electron transport chain (ETC), increases mitochondrial membrane potential (ΔΨm), differentially modulates ETC complex activities and consequently results in leak of electrons from ETC complex III and superoxide formation. The ODN-induced mitochondrial ROS yield protective antibacterial effects. Together, these studies identify a therapeutic metabolic manipulation strategy to broadly protect against pneumonia without reliance on antibiotics.

Keywords

Mice, Animals, Reactive Oxygen Species, Mitochondria, Lung, Pneumonia, Anti-Infective Agents, Membrane Potential, Mitochondrial

Comments

Supplementary Materials

PMID: 37695784