Antimicrobial mitochondrial reactive oxygen species induction by lung epithelial immunometabolic modulation

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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article numbere1011138
JournalPLoS pathogens
Volume19
Issue number9 September
DOIs
StatePublished - Sep 2023

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Virology
  • Parasitology
  • Microbiology
  • Immunology

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