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个谜。新陈代谢和 免疫是共同进化的，新陈代谢途径越来越被认为是我们免疫的关键调节因素。 系统。线粒体作为最重要的代谢细胞器也受到了人们的广泛关注。 各种免疫功能的中枢。由于它们的细菌祖先，线粒体拥有自己的基因组。 虽然mtdna本身可以触发免疫反应并直接捕获病原体，但它对 免疫因素。目前，已知我们的免疫力是由核编码的。我们最近发现了一种新基因 编码在线粒体DNA中，命名为MOTS-c(十二S rRNA中的线粒体开放阅读框架)。 MOTS-c是一种年龄依赖性多肽，调节代谢动态平衡，显著改善衰老。 小鼠的新陈代谢和体能。 在这里，我们将mots-c描述为一种一流的线粒体编码的免疫因子，它起到了抗菌剂的作用。 多肽(AMP)。与其他AMP一样，MOTS-c由多种细胞表达，包括单核细胞和 巨噬细胞。Mots-c的鉴定受到西德尼实验室先前工作的强烈影响。 Pestka(也被称为干扰素之父)，由此干扰素诱导的绝大多数mRNAs来自 单核细胞中的线粒体12S rRNA(当时还没有发现基因)。事实上，我们现在证明 MOTS-c多肽的表达是由干扰素伽马诱导的。AMPS还调节免疫细胞功能， 包括单核/巨噬细胞。这与我们的初步数据一致，根据该数据，mots-c移动到 核程序单核细胞分化以产生独特的巨噬细胞，其特征是增加 干扰素刺激基因(ISGs)和抗原提呈基因的表达。这样的“mots-c编程” 巨噬细胞杀菌能力增强。这一观察建立在我们最近关于MOTS-C的报告上，因为 一流的线粒体编码因子，移位到细胞核，直接调节压力适应 核基因表达。 在这里，我们建议检验这一假设，即MOTS-c是一种年龄依赖和干扰素诱导的线粒体- 编码AMP，一种一流的，它通过编程单核细胞分化为独特的干扰素平衡的巨噬细胞 增强了杀菌能力。我们提出了三个目的来检验这一假说：(1)确定MOTS-c- 程序性巨噬细胞在表观遗传学上为增强的抗菌反应做好了干扰素的准备，(2)测试 代谢重排增强了MOTS-c程序化巨噬细胞的杀菌能力，以及(3)决定了 MOTS-c对小鼠衰老过程中单核细胞和骨髓基质细胞功能的影响。如果成功，我们预测我们的研究 将产生广泛和持久的影响，包括(I)首次发现线粒体编码的AMP和(Ii) 鉴定可在衰老期间恢复巨噬细胞功能的新的线粒体为中心的药物类别； 线粒体基因组还没有被挖掘出来用于FDA批准的治疗方法。

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.