Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea.
Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA 90089, USA.
Cell Rep. 2021 Jul 27;36(4):109447. doi: 10.1016/j.celrep.2021.109447.
Mitochondria are principal metabolic organelles that are increasingly unveiled as immune regulators. However, it is currently not known whether mitochondrial-encoded peptides modulate T cells to induce changes in phenotype and function. In this study, we found that MOTS-c (mitochondrial open reading frame of the 12S rRNA type-c) prevented autoimmune β cell destruction by targeting T cells in non-obese diabetic (NOD) mice. MOTS-c ameliorated the development of hyperglycemia and reduced islet-infiltrating immune cells. Furthermore, adoptive transfer of T cells from MOTS-c-treated NOD mice significantly decreased the incidence of diabetes in NOD-severe combined immunodeficiency (SCID) mice. Metabolic and genomic analyses revealed that MOTS-c modulated T cell phenotype and function by regulating T cell receptor (TCR)/mTOR complex 1 (mTORC1) signaling. Type 1 diabetes (T1D) patients had a lower serum MOTS-c level than did healthy controls. Furthermore, MOTS-c reduced T cell activation by alleviating T cells from the glycolytic stress in T1D patients, suggesting therapeutic potential. Our findings indicate that MOTS-c regulates the T cell phenotype and suppresses autoimmune diabetes.
线粒体是主要的代谢细胞器，它们作为免疫调节剂的作用正逐渐被揭示。然而，目前尚不清楚线粒体编码的肽是否调节 T 细胞，从而诱导表型和功能的变化。在这项研究中，我们发现 MOTS-c（线粒体 12S rRNA 型-c 的开放阅读框）通过靶向非肥胖型糖尿病（NOD）小鼠的 T 细胞来预防自身免疫性β细胞破坏。MOTS-c 改善了高血糖的发展，并减少了胰岛浸润的免疫细胞。此外，从 MOTS-c 处理的 NOD 小鼠中过继转移 T 细胞可显著降低 NOD-严重联合免疫缺陷（SCID）小鼠糖尿病的发病率。代谢和基因组分析表明，MOTS-c 通过调节 T 细胞受体（TCR）/mTOR 复合物 1（mTORC1）信号来调节 T 细胞表型和功能。1 型糖尿病（T1D）患者的血清 MOTS-c 水平低于健康对照者。此外，MOTS-c 通过减轻 T1D 患者 T 细胞的糖酵解应激来减少 T 细胞的激活，提示其具有治疗潜力。我们的研究结果表明，MOTS-c 调节 T 细胞表型并抑制自身免疫性糖尿病。
