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.

项目总结/文摘