Study summary · research use only
MOTS-c attenuates lung ischemia-reperfusion injury via MYH9-Dependent nuclear translocation and transcriptional activation of antioxidant genes
Plain-language summary
Paraphrased from the published abstract below — not a verdict on whether anything works.
In this study using rat lung ischemia-reperfusion injury (LIRI) models, along with human patients undergoing cardiopulmonary bypass (CPB), the authors examined the mitochondrial-derived peptide MOTS-c. In rat endothelial cells, MOTS-c was reported to be most upregulated, correlating with barrier preservation and reduced oxidative stress; mechanistically, hypoxia-reoxygenation triggered ROS-dependent phosphorylation of MYH9 at Ser1943 via CK2A, enabling MOTS-c binding to MYH9-γ-Actin complexes for nuclear transport, where it interacted with promoters of antioxidant genes including HMOX1 and NQO1. In human patients, serum MOTS-c increments within 24 h post-CPB outperformed traditional biomarkers in predicting ARDS incidence (AUC = 0.885). Exogenous MOTS-c administration in rats was reported to reduce oxidative damage, inflammation, and mortality.
Abstract
Acute respiratory distress syndrome (ARDS) following cardiopulmonary bypass (CPB) is driven by oxidative stress during lung ischemia-reperfusion injury (LIRI). Mitochondrial-derived peptide MOTS-c has emerged as a regulator of mitochondrial-nuclear communication, yet its role in CPB-induced ARDS remains unclear. Here, we identify MOTS-c as a critical mediator of endothelial protection against LIRI through MYH9-dependent nuclear translocation and transcriptional activation of antioxidant genes. In rat LIRI models, endothelial cells exhibited the most significant MOTS-c upregulation, correlating with barrier preservation and reduced oxidative stress. Mechanistically, hypoxia-reoxygenation (HR) triggered reactive oxygen species (ROS)-dependent phosphorylation of MYH9 at Ser1943 via casein kinase II subunit alpha (CK2A), enabling MOTS-c binding to MYH9-γ-Actin complexes for nuclear transport. RNA sequencing (RNA-seq) combined with chromatin immunoprecipitation sequencing (ChIP-seq) revealed direct MOTS-c interaction with promoters of antioxidant genes (e.g., HMOX1, NQO1), which harbor antioxidant response elements (AREs). Clinically, serum MOTS-c increments within 24 h post-CPB (ΔMOTS-c) outperformed traditional biomarkers in predicting ARDS incidence, with multivariate models incorporating ΔMOTS-c achieving superior discriminative power (AUC = 0.885). Exogenous MOTS-c administration in rats attenuated lung injury by reducing oxidative damage, inflammation, and mortality, recapitulating endogenous protective mechanisms. Our findings establish MOTS-c as a dual-function molecule-acting via ROS-CK2A-MYH9 signaling to activate nuclear antioxidant defenses and serving as a prognostic biomarker for CPB-related complications. This study bridges mitochondrial dynamics, nuclear transcriptional regulation, and clinical outcomes, offering novel preventive avenues for IRI-associated pathologies.
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