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

基本信息

  • 批准号:
    10650823
  • 负责人:
  • 金额:
    $ 39万
  • 依托单位:
  • 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:
    2022-07-01 至 2027-04-30
  • 项目状态:
    未结题

项目摘要

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.
项目概述:线粒体是祖先之间内共生的进化产物, 真核细胞和专性需氧细菌的研究,为真核细胞带来新的功能。期间 在进化过程中,线粒体将99%以上的已知遗传物质转移到细胞核中, 除了一个小的,多拷贝的基因组,称为mtDNA。在智人中,线粒体DNA的16.6 Kbp是 编码氧化磷酸化链(OXPHOS)的13个成员和其他结构 RNA。除了通过OXPHOS产生ATP的典型作用外,线粒体也是关键的 从代谢物通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,线粒体应激与先天性免疫的异常激活有关, 细胞器成分的释放,如线粒体核酸,被胞质传感器识别为 外国的和潜在的危险。异常免疫对人类健康有着深刻的影响,是人类免疫缺陷的驱动因素。 人类疾病,如神经炎症和自身免疫。线粒体免疫已经被研究, 在体外和体内,但其触发器和效应器的完整库尚未被表征。我最近 发现了一个以前未知的有助于异常免疫的压力来源: 双链断裂(mtDSBs)。这种应激物的存在被传递到胞质区室 通过线粒体疝,一种最近描述的Bax/巴克介导的细胞器透化形式, 将线粒体内容物暴露于胞质溶胶中。mtDSB发生后,线粒体RNA --而不是受体 应激,mtDNA -通过激活传感器RIG-I启动先天免疫级联反应。我们提出的研究 本计划在过去工作的基础上提出了一些基本问题:(1)哪些线粒体DNA应激源有助于 异常免疫和功能失调的线粒体转录或翻译的影响是什么;(2)如何 线粒体疝的调节和它如何不同于其他形式的线粒体透化; (3)RIG-I的线粒体RNA激活有哪些独特的特征,它们来自哪里? 我们的目标是了解线粒体是如何整合和翻译应激信号的,特别是在 先天免疫的背景。我的实验室将探索线粒体DNA应激的不同来源并探究其机制, 效应子和线粒体部分参与免疫的胞质传感器。RIG-I是一种关键蛋白质, 它的功能是防御病毒,但它的异常激活涉及自身免疫性疾病和有益的免疫性疾病。 癌症治疗引发的抗肿瘤反应。根据我们最近的发现和以往的经验, 以及通过建立合作和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的专业知识,我们的研究计划的目的是有 对细胞应激反应的基础和转化知识的长期影响, 线粒体生物学转化为对人类健康和疾病有进一步影响的途径:先天免疫。

项目成果

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Marco Tigano其他文献

Marco Tigano的其他文献

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{{ truncateString('Marco Tigano', 18)}}的其他基金

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:
    10501418
  • 财政年份:
    2022
  • 资助金额:
    $ 39万
  • 项目类别:
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
  • 财政年份:
    2022
  • 资助金额:
    $ 39万
  • 项目类别:

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