Mitochondrial metabolism in microbial sepsis

微生物脓毒症中的线粒体代谢

• 批准号: 10214638
• 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 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10214638
• 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.

项目总结/摘要 脓毒症是重症监护病房最常见的死亡原因，是美国的主要负担 医疗保健系统。微生物感染和创伤是最常见的急性全身性 炎症反应，最终导致终末器官衰竭和败血症死亡。线粒体a 高代谢活性的细胞器，已被证明在先天性免疫功能中发挥重要作用 和炎症反应。线粒体代谢（mito-metabolism）的剧烈变化发生在 临床和实验性脓毒症。然而，导致有丝分裂代谢改变的信号机制 以及其在脓毒症发病机制中的功能性后果知之甚少。在本建议书中，我们的目标是 研究由线粒体钙信号介导的代谢异常对细胞的有害影响， 先天免疫功能在微生物脓毒症中的作用我们的初步研究发现 单向转运体（MCU）是线粒体钙摄取的关键钙通道，是细菌生长的重要调节因子， 杀死和脓毒性炎症。我们发现MCU的基因切除导致吞噬体的改善 细菌杀灭和由于升高的LC3相关吞噬作用（IL3-associated phagocytosis，IL1 β）而导致的较少的白介素1 β（IL-1 β）分泌。 从机制上讲，MCU通过促进线粒体代谢物乙酰- 通过丙酮酸脱氢酶（PDH）产生辅酶A（乙酰辅酶A）。因此，封锁MCU或 PDH功能可能代表治疗微生物败血症的有希望的治疗方案。的目标 我们的建议是研究线粒体钙信号介导的线粒体钙的功能和机制， 吞噬体细菌杀伤和炎症的代谢，这两者都是宿主的关键决定因素 在微生物败血症期间存活。我们假设：1）Mcu缺陷型小鼠乙酰辅酶A生成减少， 巨噬细胞通过蛋白质乙酰化依赖机制促进β-淀粉样蛋白形成; 2）增强β-淀粉样蛋白形成 形成促进吞噬体成员修复机制以限制过度炎性小体介导的IL-1 β 3）CPI-613对PDH的药理学抑制在治疗微生物脓毒症中是有效的。 将采用盲肠结扎和穿孔诱导的多微生物脓毒症模型来研究其作用， MCU介导的乙酰辅酶A代谢的功能。我们将测试CPI-613对PDH的抑制是否起到了 对脓毒症诱导的死亡率以及脓毒症诱导的免疫抑制的保护作用。结果进行 这些研究将为有丝分裂代谢的调节和功能提供新的见解， 导致在微生物脓毒症的治疗中鉴定新的治疗靶点。