Disease Outcome and Brain Metabolomics of Cyclophilin-D Knockout Mice in Sepsis

Takayuki Kobayashi, Hiroyuki Uchino, Eskil Elmér, Yukihiko Ogihara, Hidetoshi Fujita, Shusuke Sekine, Yusuke Ishida, Iwao Saiki, Shoichiro Shibata, Aya Kawachi

Research output: Contribution to journalArticlepeer-review

Abstract

Sepsis-associated encephalopathy (SAE) is a diffuse brain dysfunction resulting from a systemic inflammatory response to infection, but the mechanism remains unclear. The mitochondrial permeability transition pore (MPTP) could play a central role in the neuronal dysfunction, induction of apoptosis, and cell death in SAE. The mitochondrial isomerase cyclophilin D (CypD) is known to control the sensitivity of MPTP induction. We, therefore, established a cecal ligation and puncture (CLP) model, which is the gold standard in sepsis research, using CypD knockout (CypD KO) mice, and analyzed the disease phenotype and the possible molecular mechanism of SAE through metabolomic analyses of brain tissue. A comparison of adult, male wild-type, and CypD KO mice demonstrated statistically significant differences in body temperature, mortality, and histological changes. In the metabolomic analysis, the main finding was the maintenance of reduced glutathione (GSH) levels and the reduced glutathione/oxidized glutathione (GSH/GSSG) ratio in the KO animals following CLP. In conclusion, we demonstrate that CypD is implicated in the pathogenesis of SAE, possibly related to the inhibition of MPTP induction and, as a consequence, the decreased production of ROS and other free radicals, thereby protecting mitochondrial and cellular function.

Original languageEnglish
Article number961
JournalInternational Journal of Molecular Sciences
Volume23
Issue number2
DOIs
Publication statusPublished - 2022

Subject classification (UKÄ)

  • Surgery
  • Neurosciences

Free keywords

  • Cyclophilin D
  • Encephalopathy
  • Glutathione
  • Mitochondria
  • Oxidative stress

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