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

Kobayashi, Takayuki ; Uchino, Hiroyuki LU ; Elmér, Eskil LU orcid ; Ogihara, Yukihiko ; Fujita, Hidetoshi ; Sekine, Shusuke ; Ishida, Yusuke ; Saiki, Iwao ; Shibata, Shoichiro and Kawachi, Aya (2022) In International Journal of Molecular Sciences 23(2).
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,... (More)

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.

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author
; ; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Cyclophilin D, Encephalopathy, Glutathione, Mitochondria, Oxidative stress
in
International Journal of Molecular Sciences
volume
23
issue
2
article number
961
publisher
MDPI AG
external identifiers
  • pmid:35055146
  • scopus:85122834408
ISSN
1661-6596
DOI
10.3390/ijms23020961
language
English
LU publication?
yes
id
b8bf189f-2389-46b0-bcfb-06e720ebe7c4
date added to LUP
2022-02-28 14:52:45
date last changed
2024-04-27 10:40:39
@article{b8bf189f-2389-46b0-bcfb-06e720ebe7c4,
  abstract     = {{<p>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.</p>}},
  author       = {{Kobayashi, Takayuki and Uchino, Hiroyuki and Elmér, Eskil and Ogihara, Yukihiko and Fujita, Hidetoshi and Sekine, Shusuke and Ishida, Yusuke and Saiki, Iwao and Shibata, Shoichiro and Kawachi, Aya}},
  issn         = {{1661-6596}},
  keywords     = {{Cyclophilin D; Encephalopathy; Glutathione; Mitochondria; Oxidative stress}},
  language     = {{eng}},
  number       = {{2}},
  publisher    = {{MDPI AG}},
  series       = {{International Journal of Molecular Sciences}},
  title        = {{Disease Outcome and Brain Metabolomics of Cyclophilin-D Knockout Mice in Sepsis}},
  url          = {{http://dx.doi.org/10.3390/ijms23020961}},
  doi          = {{10.3390/ijms23020961}},
  volume       = {{23}},
  year         = {{2022}},
}