Mitochondrial-encoded immunity in restoring macrophage homeostasis under age-related metabolic stress

项目总结 年龄依赖性代谢功能障碍与不良适应性免疫反应有关。线粒体是关键 代谢细胞器也能够激活先天免疫信号。的组件 线粒体，如线粒体DNA(MtDNA)本身，可以触发免疫反应；然而，有 目前还没有已知的免疫调节剂编码在线粒体基因组中。MOTS-c是一种编码在 线粒体基因组，我们以前描述为代谢稳态的调节者在 衰老。MOTS-c治疗可提高脂代谢，防止饮食诱导的肥胖、脂肪肝和年龄- 依赖于小鼠的身体衰退。我们的初步数据表明，mots-c是在单核细胞中被诱导的。 激活并移位到细胞核，调节基因表达，重新编程细胞分化 单核细胞转化为巨噬细胞。这表明，mots-c在调节免疫功能方面起着至关重要的作用。 由于MOTS-c调节对代谢应激的反应，并调节巨噬细胞的表型，因此 假设MOTS-c将增强巨噬细胞维持内稳态的适应能力 在与年龄相关的脂质应激期间。在年龄和饮食诱导的代谢失调期间，总胆固醇和 组织和循环中的甘油三酯水平会增加。这些脂类可在体内诱导不良适应反应 促进慢性无菌炎症的单核细胞来源的巨噬细胞。在这里，我将测试1)MOTS的作用- C在防止分化为脂质应激的单核细胞来源的巨噬细胞的适应不良重编程方面， 2)MOTS-c对老年高脂饮食小鼠的治疗是否能防止巨噬细胞适应不良和 与慢性炎症相关的肝脏组织损伤。总的来说，这些实验将测试 范式转换的概念，免疫编码在我们两个共同进化的有丝分裂核基因组中。这 这项研究如果成功，在治疗与年龄相关的慢性炎症性疾病方面具有广泛的治疗应用 疾病。

PROJECT SUMMARY Age-dependent metabolic dysfunction is associated with maladaptive immune responses. Mitochondria are key metabolic organelles that are also capable of activating innate immune signaling. Components of the mitochondria, such as mitochondrial DNA (mtDNA) itself, can trigger immune responses; however, there are currently no known immunomodulators encoded in the mitochondrial genome. MOTS-c is a peptide encoded in the mitochondrial genome that we previously characterized as a regulator of metabolic homeostasis during aging. MOTS-c treatment increases lipid metabolism and prevents diet-induced obesity, fatty liver, and age- dependent physical decline in mice. Our preliminary data indicate that MOTS-c is induced during monocyte activation and translocates to the nucleus to regulate gene expression and reprogram the differentiation of monocytes into macrophages. This suggests that MOTS-c has a crucial role in regulating immune function. Because MOTS-c regulates responses to metabolic stress and modulates macrophage phenotype, I hypothesize that MOTS-c will enhance the adaptive capacity of macrophages to maintain homeostasis during age-related lipid stress. During age- and diet-induced metabolic dysregulation, total cholesterol and triglyceride levels increase in tissue and in circulation. These lipids can induce maladaptive responses in monocyte-derived macrophages that promote chronic sterile inflammation. Here, I will test 1) the role of MOTS- c in preventing maladaptive reprogramming of monocyte-derived macrophages differentiated with lipid stress, and 2) whether MOTS-c treatment in aged and high-fat diet fed mice prevents macrophage maladaptation and tissue damage in the liver associated with chronic inflammation. Collectively, these experiments will test the paradigm-shifting concept that immunity is encoded in both of our co-evolved mitonuclear genomes. This research, if successful, has broad therapeutic applications in the treatment of age-related chronic inflammatory diseases.