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MOTS-c mimics remote ischemic preconditioning in protecting against lung ischemia-reperfusion injury by alleviating
Dan-Dan Wang1, Bo Xu2, Jiao-Jiao Sun1
1Wuxi School of Medicine, Jiangnan University, 1800 Lihu Avenue, Wuxi, 214122, Jiangsu province, China; Department of Anesthesiology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi, Jiangsu, 214023, China.
Abstract:
Remote ischemic preconditioning (RIPC) induces the expression of unidentified protective cytokines that mitigate lung ischemia-reperfusion injury (LIRI). This study hypothesizes that MOTS-c, a mitokine with potent protective effects against mitochondrial damage, contributes to RIPC-mediated protection by alleviating endothelial barrier dysfunction. In human lung transplantation patients, serum levels of MOTS-c significantly decreased following IR injury but were markedly increased when RIPC was performed prior to transplantation. Similarly, in a mouse model of LIRI, RIPC restored serum MOTS-c levels and improved lung injury outcomes. Intravenous administration of MOTS-c in mice replicated the protective effects observed with RIPC. Mechanistic studies demonstrated that repeated hypoxia in human primary skeletal muscle immortalized cells (HPSMIC) led to the secretion of conditioned media that protected HUVECs from OGD/R-induced injury; silencing MOTS-c abolished these protective effects. Further investigations using nuclear factor erythroid 2-related factor 2 (Nrf2) knockout mice and the Nrf2 inhibitor ML385 revealed that MOTS-c exerts its protective function by increasing Nrf2 protein levels, thereby maintaining endothelial barrier integrity. In conclusion, this study identifies MOTS-c as a novel mediator of RIPC's protective effects against LIRI and highlights its potential as a therapeutic alternative for preventing lung injury and preserving vascular endothelial function.
Insights
Remote ischemic preconditioning (RIPC) protects against lung injury by increasing MOTS-c levels. This study identifies MOTS-c as a key mediator, offering potential therapeutic benefits for lung protection and vascular health.
Area of Science:
- Mitochondrial Medicine
- Vascular Biology
- Organ Transplantation
Background:
- Lung ischemia-reperfusion injury (LIRI) poses a significant clinical challenge.
- Remote ischemic preconditioning (RIPC) offers protection against LIRI through unknown mechanisms.
- Endothelial barrier dysfunction is a key factor in LIRI pathogenesis.
Purpose of the Study:
- To investigate the role of MOTS-c, a protective mitokine, in RIPC-mediated protection against LIRI.
- To determine if MOTS-c can alleviate endothelial barrier dysfunction during LIRI.
- To elucidate the molecular pathways through which MOTS-c exerts its protective effects.
Main Methods:
- Analysis of serum MOTS-c levels in human lung transplant patients and a mouse LIRI model.
- Administration of MOTS-c in vivo and in vitro to assess its protective effects.
- Mechanistic studies involving hypoxia, OGD/R injury models, MOTS-c silencing, and Nrf2 pathway analysis.
Main Results:
- RIPC significantly increased serum MOTS-c levels in patients and mice with LIRI.
- Exogenous MOTS-c administration mimicked RIPC's protective effects against LIRI.
- MOTS-c protected endothelial cells from injury by upregulating Nrf2 protein levels, maintaining barrier integrity.
Conclusions:
- MOTS-c is identified as a novel mediator of RIPC's protective effects against LIRI.
- MOTS-c plays a crucial role in preserving endothelial barrier function during lung injury.
- MOTS-c represents a potential therapeutic target for preventing LIRI and maintaining vascular health.
