Mitochondrial-Encoded Immunity in Aging

摘要 衰老与免疫功能丧失（免疫衰老）和慢性低度炎症有关 （发炎）。然而，我们衰老免疫力的机制细节在很大程度上是谜。代谢和 免疫系统已经共同进化，代谢途径越来越被认为是我们免疫系统的关键调节因子。 系统线粒体作为最重要的代谢细胞器， 各种免疫功能的枢纽。由于它们的细菌祖先，线粒体拥有自己的基因组。 虽然线粒体DNA本身可以引发免疫反应并直接捕获病原体，但尚不清楚它是否编码 免疫因素目前，我们的免疫力被认为是核编码的。我们最近发现了一种新的基因 在线粒体DNA中编码，并将其命名为MOTS-c（十二S rRNA内的线粒体ORF）。 MOTS-c是一种年龄依赖性肽，可调节代谢稳态，显著改善衰老 代谢和身体健康。 在这里，我们将MOTS-c描述为第一种由尿道编码的免疫因子， 肽（AMP）。MOTS-c与其他AMP一致，由各种细胞表达，包括单核细胞和巨噬细胞。 巨噬细胞MOTS-c的鉴定受到Sidney实验室先前工作的强烈影响 Pestka（又称“干扰素之父”），其中绝大多数由干扰素诱导的mRNAs来自 在单核细胞样细胞中的线粒体12 S rRNA（当时未鉴定出基因）。事实上，我们现在证明， MOTS-c肽的表达是由干扰素γ诱导的。AMP还调节免疫细胞功能， 包括单核细胞/巨噬细胞。这与我们的初步数据一致，其中MOTS-c移动到 核编程单核细胞分化，以产生独特的巨噬细胞，其特征在于增加 干扰素刺激基因（ISG）和抗原呈递基因的表达。这种“MOTS-c-programmed” 巨噬细胞的杀菌能力增强。这一意见是基于我们最近关于MOTS-c的报告， 第一个转位到细胞核并直接调节压力适应的神经编码因子 核基因表达 在这里，我们建议测试MOTS-c是一种年龄依赖性和IFN诱导的线粒体- 编码的AMP，一流的，编程单核细胞分化成独特的IFN-平衡的巨噬细胞， 增强杀菌能力。我们提出了三个目标来检验这一假设：（1）确定MOTS-c- 程序化巨噬细胞在表观遗传学上是“IFN-平衡”的，用于增强抗菌反应，（2）测试是否 代谢重新布线增强MOTS-c程序化巨噬细胞的杀菌能力，和（3）确定 MOTS-c在小鼠衰老过程中对单核细胞和BMDM的功能作用。如果成功，我们预测我们的研究 将产生广泛而持久的影响，包括（i）首次识别出密码编码的AMP，以及（ii） 鉴定可在衰老过程中恢复巨噬细胞功能的新的以肾脏为中心的药物类别; 线粒体基因组尚未被开发用于FDA批准的疗法。

ABSTRACT Aging is associated with a loss of immune function (immunosenescence) and chronic low-grade inflammation (inflammaging). However, the mechanistic details of our aging immunity are largely enigmatic. Metabolism and immunity have co-evolved, and metabolic pathways are increasingly appreciated as key regulators of our immune system. Mitochondria, being the most important metabolic organelle, have also gained much attention as regulatory hubs of various immune functions. Owing to their bacterial ancestry, mitochondria possess their own genome. While mtDNA itself can trigger immune responses and directly entrap pathogens, it is not known to encode for immune factors. Currently, our immunity is known to be nuclear-encoded. We have recently identified a novel gene encoded within the mitochondrial DNA and named it MOTS-c (Mitochondrial ORF within the Twelve S rRNA). MOTS-c is an age-dependent peptide that regulates metabolic homeostasis and significantly improves aging metabolism and physical fitness in mice. Here, we describe MOTS-c as the first-in-class mitochondrial-encoded immune factor that acts as an antimicrobial peptide (AMP). MOTS-c, consistent with other AMPs, is expressed by various cells including monocytes and macrophages. The identification of MOTS-c was strongly influenced by prior work from the laboratory of Sidney Pestka (aka “father of interferon”), whereby the great majority of mRNAs induced by interferon were from the mitochondrial 12S rRNA in monocyte-like cells (no genes were identified at that time). Indeed, we now demonstrate that MOTS-c peptide expression is induced by interferon gamma. AMPs also regulate immune cell functions, including monocytes/macrophages. This is consistent with our preliminary data whereby MOTS-c moves to the nucleus to program monocyte differentiation to generate unique macrophages that are characterized by increased expression of interferon-stimulated genes (ISGs) and antigen presentation genes. Such “MOTS-c-programmed” macrophages had increased bactericidal capacity. This observation builds on our recent report on MOTS-c as the first-in-class mitochondrial-encoded factor that translocates to the nucleus and directly regulates stress-adaptive nuclear gene expression. Here, we propose to test the hypothesis that MOTS-c is an age-dependent and IFN-inducible mitochondrial- encoded AMP, a first-in-class, that programs monocytes to differentiate into unique IFN-poised macrophages with enhanced bactericidal capacity. We propose three aims to test this hypothesis: (1) Determine whether MOTS-c- programmed macrophages are epigenetically “IFN-poised” for enhanced antibacterial responses, (2) Test whether metabolic rewiring enhances bactericidal capacity of MOTS-c-programmed macrophages, and (3) Determine the functional effect of MOTS-c on monocytes and BMDMs during aging in mice. If successful, we predict that our study will have broad and lasting impact including (i) the first identification of a mitochondrial-encoded AMP and (ii) the identification of novel mitochondrial-centric drug class that can restore macrophage function during aging; the mitochondrial genome has yet to be mined for FDA-approved therapeutics.