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: 10797812
• 负责人: Marco Tigano
• 金额: $ 24.21万
• 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/10797812
• 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：线粒体是祖先之间内共生的进化产物 真核细胞和专性好氧细菌为真核细胞带来了新的功能。在.期间 在他们的进化过程中，线粒体将99%以上的已知遗传物质转移到了细胞核--随着 除了被称为线粒体DNA的小的、多拷贝的基因组。在智人中，mtDNA的16.6kbp是 环状并编码13个成员的氧化磷酸化链(OXPHOS)等结构 RNA。除了线粒体在通过OXPHOS生成三磷酸腺苷的过程中的典型作用外，线粒体也是至关重要的 从代谢物流量和钙信号到细胞死亡和衰老的几个细胞过程中的利益相关者。 最近，线粒体应激被认为与先天免疫的异常激活有关，这种异常激活是通过以下途径实现的 细胞质传感器识别的细胞器成分的释放，如线粒体核酸 外来的，有潜在危险的。异常免疫对人类健康有着深远的影响，是导致 人类疾病，如神经炎和自身免疫。线粒体免疫已经被研究过了 在体外和体内，但其触发器和效应器的完整谱系尚未确定。我最近 发现了一种以前未知的有助于异常免疫的应激源：对线粒体DNA的压力 双链断裂形式(MtDSB)。这种应激源的存在被传递到胞浆隔室。 通过线粒体突出，一种最近被描述的Bax/Bak介导的细胞器通透性的形式， 使线粒体内容物暴露在细胞质中。在mtDSB之后，线粒体RNA-而不是 应激，mtDNA通过激活传感器RIG-I启动天然免疫级联反应。我们建议的研究 本计划在过去工作的基础上提出基本问题：(1)线粒体DNA应激的哪些来源有利于 异常免疫以及线粒体转录或翻译功能障碍的影响；(2) 线粒体突出受调控，它与其他形式的线粒体通透性有何不同；以及 (3)RIG-I的线粒体RNA激活有哪些显著特征，它们起源于哪里？ 我们的目标是了解线粒体是如何整合和翻译压力信号的，特别是在 先天免疫的背景。我的实验室将探索线粒体DNA压力的不同来源并询问其机制， 效应器，以及与胞浆免疫感受器相连的线粒体部分。RIG-I是一种关键蛋白质 对病毒的防御，但其异常激活既涉及自身免疫条件，也涉及有益的 癌症治疗引发的抗肿瘤反应。根据我们最近的发现和以前的经验， 以及通过建立协作并寻求高级调查人员的协助 在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 对细胞应激反应的基础知识和翻译知识的长期影响 线粒体生物学进入对人类健康和疾病有进一步影响的途径：先天免疫。