Cyclophilin D-dependent mitochondrial permeability transition amplifies inflammatory reprogramming in endotoxemia

Area of Science:

• Immunology
• Molecular Biology
• Pathology

Background:

• Lipopolysaccharide (LPS) from Gram-negative bacteria triggers systemic inflammation, leading to sepsis, organ dysfunction, and mortality.
• The liver is crucial in immunity and organ dysfunction during inflammatory responses.
• Mitochondrial permeability transition (mPT) is implicated in the pathogenesis of sepsis and shock.

Purpose of the Study:

• To investigate the role of cyclophilin D (CypD)-dependent mPT in the immunosuppressive phase of LPS-induced endotoxic shock.
• To analyze the impact of CypD on inflammatory gene expression and pathways in the liver.
• To evaluate CypD as a potential therapeutic target for endotoxic shock.

Main Methods:

• Liver RNA sequencing (RNA-seq) in wild-type and CypD-deficient mice exposed to LPS.
• Ingenuity Pathway Analysis (IPA) to interpret gene expression data.
• Assessment of survival rates, oxidative liver damage, and mitochondrial function.

Main Results:

• LPS significantly altered 2844 genes and 179 pathways, including those related to mitochondrial dysfunction, oxidative phosphorylation, nitric oxide (NO), reactive oxygen species (ROS), Nrf2, Toll-like receptors (TLRs), and tumor necrosis factor receptor (TNFR).
• CypD disruption attenuated LPS-induced changes in gene expression and pathways (TNFRs, TLRs), improved survival, and reduced oxidative liver damage.
• CypD deficiency mitigated LPS-induced suppression of mitochondrial function, gene expression, and mitochondrial DNA (mtDNA) quantity.

Conclusions:

• CypD-dependent mPT acts as an amplifier of inflammatory reprogramming and disease progression in endotoxic shock.
• Preventing mPT by disrupting CypD reduces inflammation, mitochondrial dysfunction, and lethality.
• CypD is a promising novel drug target for treating endotoxic shock and related inflammatory diseases.