MOTS-c Promotes Glycolysis via AMPK-HIF-1α-PFKFB3 Pathway to Ameliorate CPB-induced Lung Injury

Cardiopulmonary bypass (CPB) is essential during cardiac surgeries but frequently leads to lung ischemia-reperfusion injury (LIRI), a significant contributor to postoperative complications. This study investigated the protective effects of MOTS-c, a mitochondrial-derived peptide, against LIRI-induced acute lung injury (ALI), emphasizing glycolytic reprogramming and ferroptosis in pulmonary microvascular endothelial cells (PMVECs). We hypothesized that MOTS-c exerts its protective effects by regulating glycolysis and suppressing ferroptosis via metabolic signaling pathways. We conducted a prospective, controlled trial involving 107 patients undergoing CPB, evaluating plasma concentrations of MOTS-c and inflammatory markers. MOTS-c levels were significantly reduced in patients with ALI. In vivo and in vitro experiments demonstrated that MOTS-c pretreatment alleviated LIRI by enhancing glycolytic flux, reducing oxidative stress, and suppressing ferroptosis in PMVECs. MOTS-c specially reinstated the expression of PFKFB3, an essential glycolytic enzyme, thus preserving cellular energy homeostasis and diminishing lipid peroxidation. The study further emphasized the involvement of the AMPK-HIF-1α signaling pathway in the protective benefits facilitated by MOTS-c. MOTS-c elevated phosphorylated AMPKα and HIF-1α expression, indicating a vital function for these pathways in enhancing glycolysis and antioxidant defenses. Genetic and pharmacological inhibition of PFKFB3 abrogated the protective effects of MOTS-c, thereby confirming the essential role of PFKFB3-mediated glycolysis in alleviating LIRI. Our research indicates that MOTS-c could serve as a potential therapeutic agent for the prevention or treatment of LIRI-induced ALI by enhancing glycolysis, suppressing ferroptosis, and activating the AMPK-HIF-1α pathway. Future study should explore the clinical application of MOTS-c, potentially improving outcomes for patients undergoing high-risk cardiac operations.