Mitochondrial metabolism in microbial sepsis

微生物脓毒症中的线粒体代谢

• 批准号: 10457821
• 负责人: Haitao Wen
• 金额: $ 29.56万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10457821
• 关键词: Ablation; Acetyl Coenzyme A; Acetylation; Acute; Animal Model; Anti-Bacterial Agents; Anti-Inflammatory Agents; Antibacterial Response; Antiinflammatory Effect; Antisepsis; Bacterial Infections; Calcium; Calcium Channel; Calcium Signaling; Cause of Death; Cell Death; Cells; Clinical; Clinical Trials; Complex; Defense Mechanisms; Development; Electron Transport Complex III; Foundations; Future; Gene Deletion; Generations; Genetic; Goals; Healthcare Systems; Immune; Immune system; Immunosuppression; Impairment; Infection; Inflammasome; Inflammation; Inflammatory Response; Intensive Care Units; Interleukin-1 beta; Knowledge; Lead; Mass Spectrum Analysis; Mediating; Mediator of activation protein; Membrane; Metabolic; Metabolic Pathway; Metabolism; Mitochondria; Modeling; Molecular; Morbidity - disease rate; Mus; Myeloid Cells; Natural Immunity; Organ failure; Organelles; Pathogenesis; Pathway interactions; Peripheral Blood Mononuclear Cell; Phagocytosis; Phagolysosome; Phagosomes; Pharmacology; Play; Prevention; Production; Protein Acetylation; Regimen; Regulation; Role; Rupture; Sepsis; Signal Transduction; Sorting - Cell Movement; Sum; Syndrome; Testing; Therapeutic; Trauma; bactericide; base; calcium uniporter; cecal ligation puncture; cell motility; cytokine; cytokine release syndrome; efficacious treatment; immune activation; immune function; improved; innate immune function; insight; macrophage; member; microbial; mitochondrial metabolism; mortality; new therapeutic target; novel; novel strategies; polymicrobial sepsis; protective effect; pyruvate dehydrogenase; recruit; repaired; response; septic; septic patients; systemic inflammatory response; therapeutic target; uptake

Project Summary/Abstract Sepsis is the most common cause of death in intensive care units and represents a major burden to the US health care system. Microbial infection and trauma are the most common triggers of acute systemic inflammatory response that eventually leads to end organ failure and mortality in sepsis. Mitochondria, a highly metabolically active organelle, have been shown to play an essential role in the innate immune function and inflammatory response. Robust changes in mitochondrial metabolism (mito-metabolism) occur during clinical and experimental sepsis. However, the signaling mechanism leading to alterations in mito-metabolism and its functional consequence on the pathogenesis of sepsis are poorly understood. In this Proposal, we aim to study the detrimental effects of metabolic abnormalities mediated by mitochondrial calcium signaling on the innate immune function during microbial sepsis. Our preliminary studies identified the mitochondrial calcium uniporter (MCU), a key calcium channel for mitochondrial calcium uptake, as an essential regulator of bacterial killing and septic inflammation. We found that genetic ablation of MCU resulted in improved phagosomal bacterial killing and less interleukin 1β (IL-1β) secretion due to elevated LC3-associated phagocytosis (LAP). Mechanistically, MCU inhibits the assembly of LAP complex by promoting mitochondrial metabolite acetyl- coenzyme A (acetyl-CoA) generation via the pyruvate dehydrogenase (PDH). Therefore, blockade of MCU or PDH function may represent a promising therapeutic regimen for treating microbial sepsis. The goal of the proposal is to examine the function and mechanism of mitochondrial calcium signaling-mediated mito- metabolism on phagosomal bacterial killing and inflammation, both of which are key determinants of host survival during microbial sepsis. We hypothesize that 1) decreased acetyl-CoA generation in Mcu-deficient macrophages promotes LAP formation via protein acetylation-dependent mechanism; 2) enhanced LAP formation promotes phagosome member repair mechanism to limit excessive inflammasome-mediated IL-1β cleavage; 3) pharmacological inhibition of PDH by CPI-613 is effective in the treatment of microbial sepsis. Cecal ligation and puncture-induced polymicrobial sepsis model will be employed to examine the role and functions of MCU-mediated acetyl-CoA metabolism. We will test whether PDH inhibition by CPI-613 plays a protective effect on sepsis-induced mortality, as well as sepsis-induced immunosuppression. Results of these studies will provide novel insights into the regulation and function of mito-metabolism, which can potentially lead to the identification of new therapeutic targets in the treatment of microbial sepsis.

项目摘要/摘要 败血症是重症监护病房中最常见的死亡原因，代表了美国的重大燃烧 医疗保健系统。微生物感染和创伤是急性全身的最常见触发因素 炎症反应有时会导致败血症的结束器官衰竭和死亡率。线粒体，a 高度代谢活跃的细胞器已被证明在先天免疫功能中起着至关重要的作用 和炎症反应。线粒体代谢（线粒体代谢）的牢固变化发生在期间 临床和实验性败血症。但是，信号传导机制导致线索代谢发生变化 它对败血症发病机理的功能后果知之甚少。在此提案中，我们的目标 研究线粒体钙信号介导的代谢异常的有害作用对 微生物败血症期间先天免疫功能。我们的初步研究确定了线粒体钙 unitporter（MCU），线粒体钙摄取的关键钙通道，作为细菌的必要调节剂 杀戮和化粪池注射。我们发现MCU的遗传消融导致了吞噬体的改善 由于LC3相关的吞噬作用升高，细菌杀伤和少细胞介素1β（IL-1β）分泌。 从机械上讲，MCU通过促进线粒体代谢物乙酰基抑制膝盖复合物的组装 辅酶A（乙酰-COA）通过丙酮酸脱氢酶（PDH）产生。因此，MCU或 PDH功能可能代表用于治疗微生物败血症的有前途的治疗方案。目标的目标 建议是检查线粒体信号传导介导的线粒体的功能和机制 吞噬细菌杀死和注射的代谢是宿主的关键决定者 微生物败血症期间的生存。我们假设1）改善了MCU的乙酰辅酶A产生 巨噬细胞通过蛋白质乙酰化依赖性机制促进膝盖形成。 2）增强的膝盖 形成促进了吞噬体成员修复机制，以限制过量的炎性体介导的IL-1β 乳沟； 3）CPI-613对PDH的药理抑制作用可有效治疗微生物败血症。 将聘请盲肠结扎和穿刺诱导的多肌败血症模型来检查角色和 MCU介导的乙酰-COA代谢的功能。我们将测试CPI-613抑制PDH是否播放A 对败血症诱导的死亡率以及败血症诱导的免疫抑制的保护作用。这些结果 研究将提供有关线索代谢的调节和功能的新见解，这可能有可能 导致在治疗微生物败血症治疗中鉴定出新的治疗靶标。