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^mt) 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^mt and thermogenesis. Our findings indicate that POMC neuronal mitohormesis may underlie exercise-induced high-turnover metabolism.

低度线粒体应激可以促进健康和长寿，这种现象称为线粒体毒物兴奋作用。在这里，我们证明了下丘脑阿黑皮质素原 (POMC) 神经元中低水平和高水平线粒体核糖体 (mitoribosomal) 应激的相反代谢作用。 Crif1同源缺陷导致 POMC 神经元特异性严重线粒体应激导致小鼠肥胖。相比之下，POMC 神经元中Crif1异源性缺陷引起的轻度线粒体应激会导致高周转代谢和对肥胖的抵抗力。这些代谢益处是通过增强远端脂肪组织中的生热作用和线粒体未折叠蛋白反应（UPR ^mt ）来介导的。在 POMC 神经元中，部分Crif1缺陷会增加 β-内啡肽 (β-END) 和线粒体 DNA 编码肽 MOTS-c 的表达。 MOTS-c 或 β-END 的集中给药概括了Crif1异源缺陷小鼠的脂肪表型，表明这些因素是潜在的介质。一致的是，定期中等强度的跑步运动会刺激下丘脑 MOTS-c/β-END 表达，并诱导脂肪组织 UPR ^mt和生热作用。我们的研究结果表明 POMC 神经元线粒体兴奋作用可能是运动诱导的高周转代谢的基础。