Time-Resolved Metabolomics Reveals Mitochondrial Protection in Septic Liver Injury
Suzuki, Naoki ; Shibata, Shoichiro ; Sugimoto, Masahiro ; Elmer, Eskil LU
and Uchino, Hiroyuki
(2025)
In Metabolites
15(9).
- Abstract
Background/Objectives: Sepsis is a life-threatening condition characterized by organ dysfunction due to a dysregulated host response to infection. Mitochondrial dysfunction is considered a key contributor to the pathogenesis of sepsis, but its molecular mechanisms remain unclear. Methods: In this study, we used a cecal ligation and puncture (CLP) model to induce sepsis in wild-type (WT) and cyclophilin D knockout (CypD KO) mice. Liver tissues were collected at 0, 6, and 18 h post-CLP and analyzed using liquid chromatography–tandem mass spectrometry (LC-MS/MS). Results: Metabolomic profiling revealed that lactate levels significantly increased in the WT mice but remained stable in the KO mice. While AMP levels were preserved in the KO... (More)
Background/Objectives: Sepsis is a life-threatening condition characterized by organ dysfunction due to a dysregulated host response to infection. Mitochondrial dysfunction is considered a key contributor to the pathogenesis of sepsis, but its molecular mechanisms remain unclear. Methods: In this study, we used a cecal ligation and puncture (CLP) model to induce sepsis in wild-type (WT) and cyclophilin D knockout (CypD KO) mice. Liver tissues were collected at 0, 6, and 18 h post-CLP and analyzed using liquid chromatography–tandem mass spectrometry (LC-MS/MS). Results: Metabolomic profiling revealed that lactate levels significantly increased in the WT mice but remained stable in the KO mice. While AMP levels were preserved in the KO mice, these mice had significantly higher glutathione disulfide (GSSG) and spermidine concentrations than the WT mice at 18 h (p < 0.05). The levels of malondialdehyde (MDA), a marker of oxidative stress, were also significantly lower in the KO mice at 18 h (p < 0.05). These findings suggest that CypD deficiency preserves mitochondrial function, enhances resistance to oxidative stress, and mitigates septic liver injury. Conclusions: Our results highlight the potential of targeting mitochondrial permeability transition as a therapeutic strategy for sepsis.
(Less)
- author
- Suzuki, Naoki
; Shibata, Shoichiro
; Sugimoto, Masahiro
; Elmer, Eskil
LU
and Uchino, Hiroyuki
- organization
- publishing date
- 2025-09
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- cyclophilin D, liver injury, metabolomics, mitochondrial dysfunction, mitochondrial permeability transition, mouse, sepsis
- in
- Metabolites
- volume
- 15
- issue
- 9
- article number
- 600
- publisher
- MDPI AG
- external identifiers
-
- scopus:105017411986
- pmid:41002984
- ISSN
- 2218-1989
- DOI
- 10.3390/metabo15090600
- language
- English
- LU publication?
- yes
- id
- c180f16c-a440-4d2e-894e-447315bd8979
- date added to LUP
- 2025-11-27 12:36:02
- date last changed
- 2025-12-11 14:04:30
@article{c180f16c-a440-4d2e-894e-447315bd8979,
abstract = {{<p>Background/Objectives: Sepsis is a life-threatening condition characterized by organ dysfunction due to a dysregulated host response to infection. Mitochondrial dysfunction is considered a key contributor to the pathogenesis of sepsis, but its molecular mechanisms remain unclear. Methods: In this study, we used a cecal ligation and puncture (CLP) model to induce sepsis in wild-type (WT) and cyclophilin D knockout (CypD KO) mice. Liver tissues were collected at 0, 6, and 18 h post-CLP and analyzed using liquid chromatography–tandem mass spectrometry (LC-MS/MS). Results: Metabolomic profiling revealed that lactate levels significantly increased in the WT mice but remained stable in the KO mice. While AMP levels were preserved in the KO mice, these mice had significantly higher glutathione disulfide (GSSG) and spermidine concentrations than the WT mice at 18 h (p < 0.05). The levels of malondialdehyde (MDA), a marker of oxidative stress, were also significantly lower in the KO mice at 18 h (p < 0.05). These findings suggest that CypD deficiency preserves mitochondrial function, enhances resistance to oxidative stress, and mitigates septic liver injury. Conclusions: Our results highlight the potential of targeting mitochondrial permeability transition as a therapeutic strategy for sepsis.</p>}},
author = {{Suzuki, Naoki and Shibata, Shoichiro and Sugimoto, Masahiro and Elmer, Eskil and Uchino, Hiroyuki}},
issn = {{2218-1989}},
keywords = {{cyclophilin D; liver injury; metabolomics; mitochondrial dysfunction; mitochondrial permeability transition; mouse; sepsis}},
language = {{eng}},
number = {{9}},
publisher = {{MDPI AG}},
series = {{Metabolites}},
title = {{Time-Resolved Metabolomics Reveals Mitochondrial Protection in Septic Liver Injury}},
url = {{http://dx.doi.org/10.3390/metabo15090600}},
doi = {{10.3390/metabo15090600}},
volume = {{15}},
year = {{2025}},
}