Mitochondrial-Encoded Immunity in Aging

衰老中的线粒体编码免疫

基本信息

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
项目类别：
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

项目摘要

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丧失（免疫衰老）和慢性低度炎症有关（炎症）然而，我们的衰老免疫力的机制细节在很大程度上是神秘的。免疫力是共同进化的，代谢途径越来越被认为是我们免疫的关键调节因子线粒体作为最重要的代谢细胞器，也因其调节作用而受到广泛关注。由于其细菌血统，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，但尚不清楚它是否编码目前，我们的免疫力是由核编码的，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，可调节代谢稳态并显着改善衰老小鼠的新陈代谢和身体素质。在这里，我们将 MOTS-c 描述为一流的线粒体编码免疫因子，可充当抗菌剂肽（AMP），与其他 AMP 一致，由多种细胞表达，包括单核细胞和 MOTS-c 的鉴定受到 Sidney 实验室先前工作的强烈影响。 Pestka（又名“干扰素之父”），干扰素诱导的绝大多数 mRNA 来自事实上，我们现在证明了单核细胞样细胞中的线粒体 12S rRNA（当时尚未鉴定出任何基因）。 MOTS-c 肽表达是由干扰素 AMP 诱导的，也可调节免疫细胞功能，这与我们的初步数据一致，MOTS-c 转移到了细胞核对单核细胞分化进行编程，以产生独特的巨噬细胞，其特征是增加干扰素刺激基因（ISG）和抗原呈递基因的表达。这一观察结果建立在我们最近关于 MOTS-c 的报告的基础上。一流的线粒体编码因子，可转移至细胞核并直接调节应激适应性核基因表达。在这里，我们建议检验以下假设：MOTS-c 是一种年龄依赖性且 IFN 诱导的线粒体 - 编码的 AMP 是同类首创，可对单核细胞进行编程，使其分化为独特的 IFN 平衡巨噬细胞我们提出三个目标来检验这一假设：（1）确定 MOTS-c- 是否具有增强的杀菌能力。程序化巨噬细胞在表观遗传上“干扰素平衡”，可增强抗菌反应，(2) 测试是否代谢重连增强了 MOTS-c 编程巨噬细胞的细菌能力，并且 (3) 确定 MOTS-c 对小鼠衰老过程中单核细胞和 BMDM 的功能影响如果成功，我们预测我们的研究。将产生广泛而持久的影响，包括 (i) 首次鉴定线粒体编码的 AMP 和 (ii) 鉴定出能够恢复衰老过程中巨噬细胞功能的新型线粒体中心药物；线粒体基因组尚未被挖掘用于 FDA 批准的治疗方法。