MOTS-c Protects Lungs from Ischemia-Reperfusion Injury by Activating Antioxidants

Lung ischemia-reperfusion injury (LIRI) is a severe complication occurring after periods of reduced blood flow (ischemia) followed by restoration (reperfusion), often seen in lung transplantation or major thoracic surgery. This injury leads to significant inflammation, oxidative stress, and tissue damage, contributing to high morbidity and mortality. Despite its clinical importance, current therapeutic strategies for LIRI are often insufficient, and the precise mechanisms by which novel protective agents like MOTS-c exert their effects remain largely unknown, particularly regarding its nuclear signaling pathways. This study specifically addresses how MOTS-c mitigates LIRI and its underlying molecular mechanism involving MYH9 and antioxidant gene regulation.

Treatment with MOTS-c significantly attenuated LIRI, evidenced by improved lung morphology and reduced inflammatory markers. Specifically, MOTS-c administration led to a 43% reduction in lung edema (wet-to-dry weight ratio) and a 55% decrease in neutrophil infiltration compared to the saline control group (p<0.01 for both). The study's most critical finding was that MOTS-c promoted the nuclear translocation of MYH9 (myosin heavy chain 9), which subsequently activated the transcription of key antioxidant genes like Nrf2 and HO-1, resulting in a 2.5-fold increase in HO-1 expression. Furthermore, oxidative stress markers, such as malondialdehyde (MDA), were reduced by 38% in the MOTS-c treated group (p<0.001), while superoxide dismutase (SOD) activity was increased by 30% compared to untreated LIRI controls. This mechanistic insight highlights MYH9 as a novel mediator in MOTS-c's protective pathway against oxidative damage.