Cyclophilin D‐dependent mitochondrial permeability transition amplifies inflammatory reprogramming in endotoxemia. Issue 3 (13th February 2021)

• Record Type: Journal Article
• Authors: Veres, Balazs; Eros, Krisztian; Antus, Csenge; Kalman, Nikoletta; Fonai, Fruzsina; Jakus, Peter Balazs; Boros, Eva; Hegedus, Zoltan; Nagy, Istvan; Tretter, Laszlo; Gallyas, Ferenc; Sumegi, Balazs
• Is Part Of: FEBS open bio. Volume 11:Issue 3(2021)
• Page Start: 684
• Page End: 704
• Publication Date: 2021-02-13
• Subjects: antioxidant -- cyclophilin D -- endotoxin -- gene expression -- inflammation -- liver -- mitochondria -- oxidative stress -- reprogramming -- Toll‐like receptor; Molecular biology -- Periodicals; Cytology -- Periodicals; Life sciences -- Periodicals; Biological Science Disciplines -- Periodicals; Molecular Biology -- Periodicals; Cell Biology -- Periodicals; Cytology; Life sciences; Molecular biology; Periodicals; 572.805
• DOI: 10.1002/2211-5463.13091
• Languages: English
• ISSNs: 2211-5463

Abstract

Abstract : Microorganisms or LPS (lipopolysaccharide), an outer membrane component of Gram‐negative bacteria, can induce a systemic inflammatory response that leads to sepsis, multiple organ dysfunction, and mortality. Here, we investigated the role of cyclophilin D (CypD)‐dependent mitochondrial permeability transition (mPT) in the immunosuppressive phase of LPS‐induced endotoxic shock. The liver plays an important role in immunity and organ dysfunction; therefore, we used liver RNA sequencing (RNA‐seq) data, Ingenuity ® Pathway Analysis (IPA ® ) to investigate the complex role of mPT formation in inflammatory reprogramming and disease progression. LPS induced significant changes in the expression of 2844 genes, affecting 179 pathways related to mitochondrial dysfunction, defective oxidative phosphorylation, nitric oxide (NO) and reactive oxygen species (ROS) accumulation, nuclear factor, erythroid 2 like 2 (Nrf2), Toll‐like receptors (TLRs), and tumor necrosis factor α receptor (TNFR)‐mediated processes in wild‐type mice. The disruption of CypD reduced LPS‐induced alterations in gene expression and pathways involving TNFRs and TLRs, in addition to improving survival and attenuating oxidative liver damage and the related NO‐ and ROS‐producing pathways. CypD deficiency diminished the suppressive effect of LPS on mitochondrial function, nuclear‐ and mitochondrial‐encoded genes, and mitochondrial DNA (mtDNA) quantity, which could be critical in improving survival. Our data propose that CypD‐dependent mPT is an amplifier in inflammatory reprogramming and promotes disease progression. The mortality in human sepsis and shock is associated with mitochondrial dysfunction. Prevention of mPT by CypD disruption reduces inflammatory reprogramming, mitochondrial dysfunction, and lethality; therefore, CypD can be a novel drug target in endotoxic shock and related inflammatory diseases. Abstract : Disruption of CypD prevents mPT and attenuates LPS‐induced complex changes, resulting in the maintenance of stable mitochondrial structure and reduced ROS‐related signaling. The effects of CypD disruption were reduction of LPS‐induced reprogramming and protection of mitochondria and OXPHOS complexes, which have an important effect on mouse survival. CypD‐dependent mPT inhibition may be a novel drug target for inflammatory diseases.