From mtDNA stress to cellular immunity: Triggers, Mechanisms and Effectors

从线粒体DNA应激到细胞免疫：触发因素、机制和效应器

• 批准号: 10650823
• 负责人: Marco Tigano
• 金额: $ 39万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10650823
• 关键词: Aerobic Bacteria; Antitumor Response; Autoimmune Diseases; Autoimmunity; Bacteria; Biology; Calcium Signaling; Cell Aging; Cell Death; Cell Nucleus; Cell physiology; Cellular Immunity; Cellular Stress; Collaborations; Cytosol; Dangerousness; Decision Making; Disease; Eukaryotic Cell; Evolution; Generations; Genetic Materials; Genetic Transcription; Genome; Goals; Health; Homo sapiens; Human; Immunity; In Vitro; Inflammatory; Knowledge; Mediating; Mitochondria; Mitochondrial DNA; Mitochondrial RNA; Natural Immunity; Nucleic Acids; Organelles; Oxidative Phosphorylation; Pathway interactions; Permeability; Process; Production; Proteins; RNA; Research; Research Personnel; Role; Signal Transduction; Source; Stress; Technology; Translating; Translations; Virus; Work; cancer therapy; experience; genetic approach; human disease; in vivo; insight; knowledge translation; member; neuroinflammation; novel therapeutic intervention; programs; sensor; stressor

PROJECT SUMMARY: Mitochondria are the evolutionary product of the endosymbiosis between the ancestral eukaryotic cell and an obligate aerobe bacterium, which brought new functionalities to eukaryotic cells. During their evolution, mitochondria transferred more than 99% of their known genetic material to the nucleus – with the exception of a small, multi-copy genome referred to as mtDNA. In Homo sapiens, the 16.6 Kbp of mtDNA is circular and encodes for 13 members of the oxidative phosphorylation chain (OXPHOS) and other structural RNAs. Beyond their canonical role in the generation of ATP through OXPHOS, the mitochondria are also critical stakeholders in several cellular processes from metabolite fluxes and calcium signaling to cell death and aging. Recently, mitochondrial stress has been implicated in the aberrant activation of innate immunity, mediated by the release of organellar components, such as mitochondrial nucleic acids, recognized by cytosolic sensors as foreign and potentially dangerous. Aberrant immunity has deep implications in human health and is a driver of human diseases, such as neuroinflammation and autoimmunity. Mitochondrial immunity has been studied both in vitro and in vivo, but the complete repertoire of its triggers and effectors has yet to be characterized. I recently uncovered a previously unknown source of stress conducive to aberrant immunity: stress to the mtDNA in the form of double-stranded breaks (mtDSBs). The presence of this stressor is relayed to the cytosolic compartment via mitochondrial herniation, a recently described form of Bax/Bak mediated organelle permeabilization, that exposes mitochondrial contents to the cytosol. After mtDSBs, mitochondrial RNA – rather than the recipient of the stress, mtDNA – initiated the innate immunity cascade by activating the sensor RIG-I. Our proposed research plan builds on this past work to ask essential questions: (1) which sources of mtDNA stress are conducive to aberrant immunity and what is the impact of dysfunctional mitochondrial transcription or translation; (2) how is mitochondrial herniation regulated and how does it differ from other forms of mitochondrial permeabilization; and (3) what are the distinctive features of mitochondrial RNA activation of RIG-I and where do they originate? Our goal is to understand how mitochondria integrate and translate stress signals, particularly in the context of innate immunity. My lab will probe different sources of mtDNA stress and interrogate the mechanisms, effectors, and mitochondrial moieties engaging the cytosolic sensors of immunity. RIG-I is a key protein for the defense against viruses, but its aberrant activation is involved in both autoimmune conditions and the beneficial anti-tumor responses elicited by cancer treatments. By building upon our recent findings and prior experience, as well as by establishing collaborations and seeking the assistance of senior investigators with advanced expertise in both mitochondrial biology and the key technologies proposed, our research program aims to have long-lasting impacts on the foundational and translational knowledge of cellular stress responses going beyond mitochondrial biology into a pathway with further implications in human health and disease: innate immunity.

项目摘要：线粒体是祖先内共生的进化产物 真核细胞和强大的可氧化物细菌，为真核细胞带来了新的功能。期间 它们的进化，线粒体将其已知遗传物质的99％以上转移到了核中 - 一个小的多拷贝基因组除外，称为mtDNA。在智人中，mtDNA的16.6 kbp是 氧化磷酸化链（OXPHOS）和其他结构的13个成员的圆形和编码 RNA。除了其在ATP通过OXPHOS生成中的典型作用之外，线粒体也很关键 利益相关者在几个细胞过程中，从代谢物通量和钙信号传导到细胞死亡和衰老。 最近，线粒体应力在异常的先天免疫激活中暗示，由 有机成分的释放，例如线粒体核酸，被胞质传感器识别为 外国和潜在危险。异常免疫对人类健康具有深远的影响，是 人类疾病，例如神经炎症和自身免疫性。线粒体免疫组织都已经研究了 体外和体内，但其触发因素和效果的完整曲目尚未表征。我最近 发现了先前未知的应力来源，导致对异常免疫力：对mtDNA的压力 双链断裂的形式（MTDSB）。该压力源的存在被传递到胞质室 通过线粒体疝，最近描述的Bax/Bak介导细胞器透化的形式，该形式 暴露于细胞质的线粒体含量。 MTDSB后，线粒体RNA - 而不是接受者 压力mtDNA - 通过激活传感器rig-i引发了先天免疫级联。我们提出的研究 计划以过去的工作为基础提出基本问题：（1）进行哪些MTDNA压力来进行 异常免疫力以及功能失调的线粒体转录或翻译的影响； （2）如何 线粒体疝受调节，与其他形式的线粒体通透性不同；和 （3）RIG-I的线粒体RNA激活的独特特征是什么？它们起源于哪里？ 我们的目标是了解线粒体如何整合和翻译压力信号，尤其是在 先天免疫的背景。我的实验室将探测不同的mtDNA应力来源，并询问机制， 效应子和线粒体部分与免疫的胞质传感器相关。 rig-i是关键蛋白 防御病毒的防御，但其异常激活涉及自身免疫性条件和有益的 癌症治疗引起的抗肿瘤反应。通过基于我们最近的发现和先前的经验， 以及建立合作并寻求高级调查员的协助 线粒体生物学和提出的关键技术方面的专业知识，我们的研究计划旨在拥有 对细胞压力反应的基础和翻译知识的长期影响超出 线粒体生物学进入一条对人类健康和疾病的进一步影响的途径：先天免疫学。