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Nitric oxide and mitochondrial biogenesis in sepsis

脓毒症中的一氧化氮和线粒体生物发生

基本信息

批准号：
7743390
负责人：
CLAUDE A PIANTADOSI
金额：
$ 25.74万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-12-15 至 2010-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7743390
关键词：
Acute Apoptosis Appearance Biogenesis Biology Cell Survival Cells Chemistry Communication DNA copy number Data Enterobacteriaceae Failure Financial compensation Fostering Functional disorder Genetic Transcription Hepatic Human Immune response Inflammation Inflammatory Response Injury Intervention Knockout Mice Knowledge Kupffer Cells Lactic Acidosis Liver Measures Mediator of activation protein Mitochondria Mitochondrial DNA Molecular Multiple Organ Failure Necrosis Nitric Oxide Nitric Oxide Synthase Nitrogen Nuclear Organ Oxidation-Reduction Oxygen Pathogenesis Pathology Patients Phase Physiological Process Production Protein Isoforms Proteins Proteome Regulation Resolution Respiration Role Sepsis Series Side Signal Transduction Source Stress Supporting Cell Testing Time Transcriptional Activation Work base cell injury cell killing factor A falls human NOS2A protein mitochondrial dysfunction mtTF1 transcription factor nrf1 protein nuclear respiratory factor prevent response response marker restoration septic transcription factor

项目摘要

This is an amended application to study the basic mechanisms of action of nitric oxide (NO) in mitochondrial biogenesis in the liver in sepsis. NO synthase induction is fundamental to the sepsis-induced immune response but the production reactive nitrogen and oxygen species (RNS, ROS) is a stress that drives mitochondrial dysfunction and is important in the pathogenesis of multiple organ failure (MOF). We have discovered that RNS and ROS production in experimental sepsis damage mitochondrial DNA (mtDNA), thereby impairing mitochondrial transcription, proteome fidelity, and mitochondrial function. This mitochondrial damage stimulates cellular compensation involvingmitochondrialbiogenesis, which requires activation ofmitochondrial transcription factor A (mtTFA) and two nuclear transcription factors, nuclear respiratory factor-1 and -2 (NRF-1 and -2),and a co-activator, PGC-1. These unique cell responses, under nuclear control, signify a crucial side of mitochondrial biology modulated by RNS and ROS, and one that is pro-survival. Though we still know very little about regulation of biogenesis in inflammation or its disruption in sepsis, our data show clearly that mitochondrial pathology is not limited simply to the NO-chemistry that damages mitochondria and kills cells. Therefore, we propose to test the hypothesis that iNOS-stimulated mitochondrial biogenesis opposes cell necrosis in sepsis, and thereby, regulation of biogenesis is an important determinant of cell survival. To test this hypothesis we propose three Specific Aims: Aim 1: Measure the contribution of iNOS to the pathogenesis of damage to hepatic mitochondrial DNA and proteins in sepsis using wild type and iNOS knockout mice; Aim 2: Define the importance of iNOS in mitochondrial transcription factor A (Tfam) activation and the restoration of hepatic mtDNA copy number and transcription in wild type and iNOS knockout mice in sepsis; Aim 3: Determine the contribution of iNOS to nuclear transcriptional activation of biogenesis in sepsis via NRF-1 and NRF-2 expression in wild type and iNOS knockout mice. This work will provide a better mechanistic understanding of the nuclear-mitochondrial communication during the host inflammatory response, which should help foster new molecular strategies to assess the ability of mitochondrial response markers to predict MOF and to guide interventions to prevent and eventually to treat sepsis-induced MOF.

这是一种研究线粒体中一氧化氮(NO)基本作用机制的改进应用脓毒症时肝脏的生物发生。NO合酶诱导是脓毒症诱导免疫反应的基础但产生的活性氮和氧物种(RNS，ROS)是驱动线粒体的压力功能障碍，在多器官衰竭(MOF)的发病机制中起重要作用。我们发现，实验性脓毒症时RNS和ROS的产生损伤线粒体DNA(MtDNA)，从而损害线粒体转录、蛋白质组保真度和线粒体功能。这种线粒体损伤刺激涉及线粒体生物发生的细胞补偿，这需要激活线粒体转录因子A(MtTFA)和两个核转录因子-1和-2 (NRF-1和-2)和共激活剂PGC-1。这些独特的细胞反应，在核控制下，意味着线粒体生物学中受RNS和ROS调控的关键方面，也是支持生存的方面。虽然我们我们的数据显示，我们对炎症中生物发生的调节或其在脓毒症中的破坏知之甚少显然，线粒体病理学并不局限于破坏线粒体和杀死细胞。因此，我们建议检验iNOS刺激线粒体生物发生的假设反对脓毒症中的细胞坏死，因此，生物发生的调节是细胞存活。为了检验这一假设，我们提出了三个具体目标：目标1：衡量诱导型一氧化氮合酶在脓毒症肝线粒体DNA和蛋白质损伤发病机制中的作用和iNOS基因敲除小鼠；目标2：确定iNOS在线粒体转录因子A中的重要性 (TFAM)激活及肝线粒体DNA拷贝数和转录的恢复脓毒症中iNOS基因敲除小鼠；目的3：确定iNOS在核转录中的作用通过野生型和iNOS基因敲除小鼠NRF-1和NRF-2的表达激活脓毒症的生物发生。这项工作将提供一个更好的机制理解核-线粒体通讯在宿主炎症反应，这应该有助于培养新的分子策略来评估线粒体反应标记物预测多器官功能衰竭并指导干预措施预防并最终治疗脓毒症诱导的多器官功能衰竭。

项目成果

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Regulation of mitochondrial processes by protein S-nitrosylation.

DOI：
10.1016/j.bbagen.2011.03.008
发表时间：
2012-06
期刊：
BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS
影响因子：
3
作者：
Piantadosi, Claude A.
通讯作者：
Piantadosi, Claude A.

Nitric oxide synthase-2 induction optimizes cardiac mitochondrial biogenesis after endotoxemia.

DOI：
10.1016/j.freeradbiomed.2008.11.007
发表时间：
2009-03-01
期刊：
FREE RADICAL BIOLOGY AND MEDICINE
影响因子：
7.4
作者：
Reynolds, Crystal M.;Suliman, Hagir B.;Hollingsworth, John W.;Welty-Wolf, Karen E.;Carraway, Martha Sue;Piantadosi, Claude A.
通讯作者：
Piantadosi, Claude A.

Nitric oxide synthase-2 regulates mitochondrial Hsp60 chaperone function during bacterial peritonitis in mice.

DOI：
10.1016/j.freeradbiomed.2009.12.019
发表时间：
2010-03-01
期刊：
FREE RADICAL BIOLOGY AND MEDICINE
影响因子：
7.4
作者：
Suliman, Hagir B.;Babiker, Abdelwahid;Withers, Crystal M.;Sweeney, Timothy E.;Carraway, Martha S.;Tatro, Lynn G.;Bartz, Raquel R.;Welty-Wolf, Karen E.;Piantadosi, Claude A.
通讯作者：
Piantadosi, Claude A.

Erythropoietin activates mitochondrial biogenesis and couples red cell mass to mitochondrial mass in the heart.