Kong Byung Soo, Lee Hyunsuk, L'Yi Sehi, Hong Serin, Cho Young Min
Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea.
Department of Molecular Metabolism, T.H. Chan School of Public Health, Harvard University, Boston, MA, 02115, USA.
Exp Mol Med. 2025 Aug;57(8):1861-1877. doi: 10.1038/s12276-025-01521-1. Epub 2025 Aug 25.
Mitochondria are crucial for cell survival and function, partly through peptides encoded by the mitochondrial genome. Although mitochondrial dysfunction is a hallmark of age-related diseases and senescence, the role of mitochondrial-genome-encoded peptides in pancreatic β-cell senescence during type 1 and type 2 diabetes pathogenesis is largely unexplored. Here we show that MOTS-c levels decrease with aging and senescence in pancreatic islet cells. Treating aged C57BL/6 mouse pancreatic islets with MOTS-c reduced pancreatic islet senescence by modulating nuclear gene expression and metabolites involved in β-cell senescence. MOTS-c treatment improved pancreatic islet senescence and glucose intolerance in S961-treated C57BL/6 and in nonobese diabetic mice. In humans, circulating MOTS-c levels are lower in type 2 diabetes patients compared with healthy controls. Our findings suggest that mitochondrial-encoded MOTS-c regulate pancreatic islet cell senescence and that MOTS-c could act as a senotherapeutic agent to prevent pancreatic islet cell senescence and diabetes progression.
线粒体对于细胞存活和功能至关重要，部分原因是通过线粒体基因组编码的肽来实现的。尽管线粒体功能障碍是衰老相关疾病和衰老的一个标志，但在1型和2型糖尿病发病机制中，线粒体基因组编码的肽在胰腺β细胞衰老中的作用在很大程度上尚未得到探索。在这里，我们表明，MOTS-c水平在胰腺胰岛细胞中随着衰老和老化而降低。用MOTS-c处理老年C57BL/6小鼠胰岛，通过调节与β细胞衰老相关的核基因表达和代谢产物，减少了胰腺胰岛衰老。MOTS-c治疗改善了S961处理的C57BL/6和非肥胖糖尿病小鼠的胰腺胰岛衰老和葡萄糖不耐受。在人类中，与健康对照相比，2型糖尿病患者的循环MOTS-c水平较低。我们的研究结果表明，线粒体编码的MOTS-c调节胰腺胰岛细胞衰老，并且MOTS-c可以作为一种衰老治疗剂来预防胰腺胰岛细胞衰老和糖尿病进展。
