Mitochondrial-Encoded Immunity in Aging

衰老中的线粒体编码免疫

• 批准号: 10688318
• 负责人: Changhan Lee
• 金额: $ 33.83万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-30 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10688318
• 关键词: Aconitic Acid; Age; Aging; Anti-Bacterial Agents; Antibacterial Response; Antibody Therapy; Antigen Presentation; Attention; Bacterial Infections; Bone Marrow; Carboxy-Lyases; Cations; Cell Nucleus; Cell physiology; Cells; Chronic; Data; Disease; Epigenetic Process; Exposure to; FDA approved; Fathers; Free Radicals; Functional disorder; Gene Expression; Genes; Genome; Glycolysis; Goals; Histones; Homeostasis; Human; Immune; Immune response; Immune system; Immunity; Immunologic Factors; Impairment; Infection; Inflammaging; Inflammation; Inflammatory; Interferon Type II; Interferons; Knockout Mice; Laboratories; Life; Longevity; Measurement; Measures; Messenger RNA; Metabolic; Metabolic Pathway; Metabolism; Mitochondria; Mitochondrial DNA; Mus; NADPH Oxidase; Names; Nuclear; Open Reading Frames; Organelles; Peptides; Pharmaceutical Preparations; Physical Capacity; Physical Fitness; Play; Predisposition; RNA, ribosomal, 12S; Reporting; Rest; Ribosomal RNA; Role; Running; Signal Transduction; Sterility; Stress; Testing; Therapeutic; Time; Tissues; Withdrawal; Work; age related; aged; antimicrobial; antimicrobial peptide; bactericide; base; fluorescence imaging; functional genomics; immune function; immunoregulation; immunosenescence; improved; macrophage; metabolomics; middle age; mitochondrial genome; monocyte; mouse model; mutant; novel; pathogen; programs; response; sex; single-cell RNA sequencing; stable isotope

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.

抽象的 衰老与免疫功能（免疫衰老）和慢性低度炎症有关 （发炎）。但是，我们的衰老免疫力的机械细节在很大程度上是神秘的。代谢和 免疫力已经共同发展，代谢途径越来越被视为免疫的关键调节剂 系统。线粒体是最重要的代谢细胞器，作为调节 各种免疫学功能的枢纽。由于其细菌血统，线粒体具有自己的基因组。 虽然mtDNA本身可以触发免疫调查并直接捕获病原体，但尚不知道它的编码 免疫因素。目前，我们的免疫学已被核编码。我们最近确定了一个新型基因 编码在线粒体DNA中，并将其命名为Mots-C（十二个S rRNA中的线粒体ORF）。 MOTS-C是一种依赖年龄的肽，可调节代谢稳态并显着改善衰老 小鼠的代谢和身体健康。 在这里，我们将MOTS-C描述为首先用作抗菌剂的线粒体编码的免疫因子 肽（AMP）。与其他AMP一致的Mots-C由包括单核细胞和 巨噬细胞。 MOTS-C的识别受Sidney实验室的先前工作的强烈影响 Pestka（又名“干扰之父”），因此，由干扰引起的绝大多数mRNA来自 单核细胞样细胞中的线粒体12S rRNA（当时尚未鉴定基因）。确实，我们现在证明 该MOTS-C肽表达是由干扰素伽马诱导的。放大器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，MOTS-C移至 编程单核细胞分化的细胞核以产生独特的巨噬细胞，这些巨噬细胞的特征是增加 干扰素刺激的基因（ISGS）和抗原表现基因的表达。这样的“ mots-c程序” 巨噬细胞的杀菌能力增加。该观察结果是基于我们最近关于MOTS-C的报告 一级线粒体编码的因子易位到细胞核并直接调节应力自适应 核基因表达。 在这里，我们建议检验以下假设：MOTS-C是年龄依赖性且IFN诱导的线粒体 - 编码AMP，一类，对单核细胞进行编程，以分化为独特的IFN伪巨噬细胞 增强的杀菌能力。我们提出了三个旨在检验这一假设的目的：（1）确定MOTS-C-是否是否 用于增强抗菌反应的程序巨噬细胞在表观遗传上是“ IFN伪造的”，（2）测试是否是否测试是否是否 代谢重新布线增强了MOTS-C型巨噬细胞的杀菌能力，（3）确定 MOTS-C对小鼠衰老过程中单核细胞和BMDM的功能效应。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）首次识别线粒体编码的AMP和（ii） 鉴定新的以线粒体为中心的药物类，可以在衰老期间恢复巨噬细胞功能；这 线粒体基因组尚未开采用于FDA批准的治疗。