MOTS-c attenuates lung ischemia-reperfusion injury via MYH9-Dependent nuclear translocation and transcriptional activation of antioxidant genes.

Summary

In rat LIRI, MOTS-c translocates to the nucleus via MYH9 following ROS/CK2A-dependent MYH9 phosphorylation and directly engages ARE-containing promoters (e.g., HMOX1, NQO1) to activate antioxidant defenses. Clinically, perioperative ΔMOTS-c within 24 h post-CPB predicted ARDS (AUC 0.885), and exogenous MOTS-c reduced lung injury, inflammation, oxidative damage, and mortality in vivo.

Key Findings

• Endothelial cells showed prominent MOTS-c upregulation in rat LIRI with barrier preservation and reduced oxidative stress.
• ROS-CK2A-mediated phosphorylation of MYH9 (Ser1943) enabled MOTS-c binding to MYH9–γ-Actin complexes for nuclear transport.
• ChIP-seq and RNA-seq demonstrated MOTS-c occupancy at ARE-containing promoters (HMOX1, NQO1) and activation of antioxidant programs.
• Perioperative ΔMOTS-c within 24 h post-CPB predicted ARDS with AUC 0.885; multivariate models with ΔMOTS-c outperformed traditional biomarkers.
• Exogenous MOTS-c administration reduced lung injury, inflammation, oxidative damage, and mortality in vivo.

Clinical Implications

ΔMOTS-c could enable early risk stratification for CPB-associated ARDS and guide preventive strategies; MOTS-c analogs merit evaluation as prophylactic adjuncts to reduce LIRI-related complications.

Limitations

• Human cohort size and external validation details are not reported, limiting generalizability
• No randomized clinical testing of MOTS-c therapy; species differences may affect translation

Future Directions

Prospective multicenter validation of ΔMOTS-c for ARDS prediction and phase I/II trials of MOTS-c or analogs for perioperative prophylaxis in high-risk CPB patients.