Melatonin attenuates liver ischemia-reperfusion injury via inhibiting the PGAM5-mPTP pathway.
Melatonin
/ pharmacology
Reperfusion Injury
/ metabolism
Animals
Phosphoprotein Phosphatases
/ metabolism
Liver
/ metabolism
Male
Mitochondrial Permeability Transition Pore
/ metabolism
Mice
Hepatocytes
/ metabolism
Mitochondrial Membrane Transport Proteins
/ metabolism
Apoptosis
/ drug effects
Signal Transduction
/ drug effects
Oxidative Stress
/ drug effects
Mice, Inbred C57BL
Journal
PloS one
ISSN: 1932-6203
Titre abrégé: PLoS One
Pays: United States
ID NLM: 101285081
Informations de publication
Date de publication:
2024
2024
Historique:
received:
10
05
2024
accepted:
14
10
2024
medline:
29
10
2024
pubmed:
29
10
2024
entrez:
29
10
2024
Statut:
epublish
Résumé
Phosphoglycerate mutase/protein phosphatase (PGAM5)-mediated cell death plays an important role in multiple liver diseases. However, few studies have confirmed the regulatory mechanism of melatonin acting on PGAM5-mediated cell death in the context of liver ischemia-reperfusion (I/R) injury. The liver I/R injury model and cell hypoxia-reoxygenation model were established after melatonin pretreatment. Liver injury, cell activity, cell apoptosis, oxidative stress index, and PGAM5 protein expression were detected. To investigate the role of PGAM5 in melatonin-mediated liver protection during I/R injury, PGAM5 silencing, and overexpression were performed before melatonin pretreatment. Our results indicated that PGAM5 was significantly elevated by I/R injury, and predominantly localized in the necrosis area. However, treatment with melatonin blocked PGAM5 activation and conferred a survival advantage of hepatocytes in liver I/R injury, similar to the results achieved by silencing PGAM5. In terms of mechanism, we illustrated that activated PGAM5 promoted mitochondrial permeability transition pore (mPTP) opening, and administration of melatonin inhibited mPTP opening and interrupted hepatocytes death via blocking PGAM5. Our data indicated that the PGAM5-mPTP axis is responsible for I/R-induced liver injury. In contrast, melatonin supplementation blocked the PGAM5-mPTP axis and thus decreased cell death, providing a protective advantage to hepatocytes in I/R. These results established a new paradigm in melatonin-mediated hepatocyte protection under the burden of I/R attack.
Identifiants
pubmed: 39471139
doi: 10.1371/journal.pone.0312853
pii: PONE-D-24-18786
pmc: PMC11521291
doi:
Substances chimiques
Melatonin
JL5DK93RCL
Phosphoprotein Phosphatases
EC 3.1.3.16
PGAM5 protein, mouse
EC 3.1.3.16
Mitochondrial Permeability Transition Pore
0
Mitochondrial Membrane Transport Proteins
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e0312853Informations de copyright
Copyright: © 2024 Shi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
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