Asan Institute for Life Science, University of Ulsan College of Medicine, Seoul 05505, Korea.
Division of Endocrinology and Metabolism, Department of Internal Medicine, Diabetes Center, Asan Medical Center and University of Ulsan College of Medicine, Seoul 05505, Korea.
Cell Metab. 2021 Feb 2;33(2):334-349.e6. doi: 10.1016/j.cmet.2021.01.003.
Low-grade mitochondrial stress can promote health and longevity, a phenomenon termed mitohormesis. Here, we demonstrate the opposing metabolic effects of low-level and high-level mitochondrial ribosomal (mitoribosomal) stress in hypothalamic proopiomelanocortin (POMC) neurons. POMC neuron-specific severe mitoribosomal stress due to Crif1 homodeficiency causes obesity in mice. By contrast, mild mitoribosomal stress caused by Crif1 heterodeficiency in POMC neurons leads to high-turnover metabolism and resistance to obesity. These metabolic benefits are mediated by enhanced thermogenesis and mitochondrial unfolded protein responses (UPR) in distal adipose tissues. In POMC neurons, partial Crif1 deficiency increases the expression of β-endorphin (β-END) and mitochondrial DNA-encoded peptide MOTS-c. Central administration of MOTS-c or β-END recapitulates the adipose phenotype of Crif1 heterodeficient mice, suggesting these factors as potential mediators. Consistently, regular running exercise at moderate intensity stimulates hypothalamic MOTS-c/β-END expression and induces adipose tissue UPR and thermogenesis. Our findings indicate that POMC neuronal mitohormesis may underlie exercise-induced high-turnover metabolism.
低水平线粒体应激可促进健康和长寿，这种现象被称为线粒体应激。在这里，我们证明了低水平和高水平线粒体核糖体（mitoribosomal）应激在下丘脑前阿黑皮素原（POMC）神经元中的相反代谢效应。由于 Crif1 同源缺陷导致的 POMC 神经元特异性严重线粒体核糖体应激会导致小鼠肥胖。相比之下，POMC 神经元中由 Crif1 杂合缺陷引起的轻度线粒体核糖体应激会导致高代谢周转率和肥胖抵抗。这些代谢益处是通过增强远端脂肪组织的产热和线粒体未折叠蛋白反应（UPR）介导的。在 POMC 神经元中，部分 Crif1 缺乏会增加β-内啡肽（β-END）和线粒体 DNA 编码肽 MOTS-c 的表达。MOTS-c 或 β-END 的中枢给药再现了 Crif1 杂合缺陷小鼠的脂肪表型，表明这些因素可能是潜在的介导物。一致地，适度强度的常规跑步运动刺激下丘脑 MOTS-c/β-END 的表达，并诱导脂肪组织 UPR 和产热。我们的研究结果表明，POMC 神经元的线粒体应激可能是运动诱导的高代谢周转率的基础。
