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

作者：Zihao Shen, Peng Lü, Wanjun Jin, Ziang Wen, Yuanpu Qi, Xiangyü Li, Mingyu Chu, Xin Yao, Minchao Wu, Ao Wang, Xiao Zhang, Wei Wang, Meijuan Song, Xiaowei Wang · 发表于：American Journal of Respiratory Cell and Molecular Biology · 年份：2025 · DOI：10.1165/rcmb.2024-0533oc · 被引用次数：17 · 研究领域：Cancer, Hypoxia, and Metabolism、Mesenchymal stem cell research、Metabolism, Diabetes, and Cancer

Abstract Cardiopulmonary bypass (CPB) is essential during cardiac surgery but frequently leads to lung ischemia–reperfusion injury (LIRI), a significant contributor to postoperative complications. We investigated the protective effects of mitochondrial open reading frame of the 12S ribosomal RNA type C (MOTS-c), a mitochondrial-derived peptide, against LIRI-induced acute lung injury (ALI), emphasizing glycolytic reprogramming and ferroptosis in pulmonary microvascular endothelial cells. 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 concentrations 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 pulmonary microvascular endothelial cells. In particular, MOTS-c reinstated the expression of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), an essential glycolytic enzyme, thus preserving cellular energy homeostasis and diminishing lipid peroxidation. The findings further emphasize the involvement of the AMPK (AMP-activated protein kinase)–hypoxia inducible factor-1α (HIF-1α) signaling pathway in the protective benefits facilitated by MOTS-c...