Impact of mitochondrial structure on cellular homeostasis and hepatic injury

线粒体结构对细胞稳态和肝损伤的影响

• 批准号: 10549994
• 负责人: Dhanendra Tomar
• 金额: $ 24.9万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-16 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10549994
• 关键词: Architecture; Automobile Driving; Binding; Bioenergetics; Biogenesis; Biology; Calcium; Cell Death; Cell Survival; Cell membrane; Cells; Cessation of life; Complex; Coupled; Data; Development; EF Hand Motifs; EF-Hand Domain; Endoplasmic Reticulum; Equilibrium; Event; Generations; Genetic; Genetic Models; Hepatic; Hepatocyte; Homeostasis; Impairment; In Vitro; Knock-in; Knock-in Mouse; Lead; Link; Lipids; Liver; Maintenance; Mediating; Membrane; Membrane Potentials; Membrane Proteins; Metabolism; Mitochondria; Mitochondrial Swelling; Molecular; Mus; Mutation; Necrosis; Necrosis Induction; Nutrient; Operative Surgical Procedures; Organ failure; Organelles; Outer Mitochondrial Membrane; Output; Oxidation-Reduction; Pathogenicity; Physiological; Physiological Processes; Play; Positioning Attribute; Post-Translational Protein Processing; Process; Protein Biochemistry; Proteins; Recycling; Regulation; Reperfusion Injury; Reporter; Reporting; Research; Resistance; Role; Rupture; Shapes; Signal Pathway; Signal Transduction; Stress; Structure; System; Testing; Tissues; Transplantation; Ubiquitin; base; career; hepatic necrosis; hormone regulation; in vivo; ischemic injury; live cell imaging; liver injury; liver ischemia; mitochondrial membrane; mitochondrial permeability transition pore; mouse model; novel; novel therapeutic intervention; programs; response; rho GTP-Binding Proteins; skills; tool; trafficking; uptake

Abstract: In the cellular system, mitochondria form an intricate network of interconnected mitochondrion of different shapes and sizes. The mitochondrion forms close contact with other cellular organelles which are essential in maintaining the mitochondrial integrity as well as the functions. Emerging evidence suggests the complexity of the mitochondrial architecture and processes involved in the maintenance of functional mitochondrial pool in the cell. The mitochondrial architecture is regulated by various pathophysiological signals like nutrient availability, hormonal regulation, and stress conditions which regulates cytosolic calcium (cCa2+) dynamics as well. The dynamic changes in the cCa2+ regulate mitochondrial shape through a Ca2+-sensing mitochondrial outer membrane-anchored EF-hand containing protein Miro1. This phenomenon termed as the mitochondrial shape transition (MiST) is independent of Miro1's role in mitochondrial trafficking and Drp1-induced mitochondrial fission. Although Ca2+ signals fine-tune the mitochondrial bioenergetic output, and sustained elevation of cCa2+ drives excessive mitochondrial Ca2+ uptake which is a prerequisite for the opening of mitochondrial permeability transition pore (MPTP), mitochondrial swelling, plasma membrane rupture, and necrotic cell death. Preliminary data suggest that in response to MiST, endoplasmic reticulum (ER)-mitochondrial tethering is increased which may be essential for both MPTP opening and the mitophagic response. In response to hepatic ischemia-reperfusion injury (IRI), MPTP opening leads to the onset of hepatic necrosis and subsequent organ failure. Mitochondrial integrity is crucial for hepatic function and survival after IRI. However, the underlying molecular mechanism for the maintenance of mitochondrial integrity is largely unidentified. Therefore,we will mechanistically examinethe link betweenMiST, MPTP, and mitophagy with a particular emphasis on the role of Miro1 in MPTP formation, initiation of mitophagy, and induction of necrosis in response to the hepatic IRI. The project outline will enable the development of essential skills and expertise needed to develop PI's independent research program focusing on the mitochondrial biology in the hepatic system.

抽象的： 在蜂窝系统中，线粒体形成了一个复杂的网络网络的网络 不同的形状和大小。线粒体与其他细胞细胞器紧密接触 这对于维持线粒体完整性以及功能至关重要。新兴 有证据表明线粒体结构和涉及的过程的复杂性 维护细胞中功能性线粒体池。线粒体架构是 受各种病理生理信号（例如养分可用性，荷尔蒙调节）的调节， 以及调节胞质钙（CCA2+）动力学的应力条件。动态 CCA2+通过Ca2+ sensing线粒体外部调节线粒体形状的变化 膜锚定的EF手含有蛋白miro1。这种现象称为 线粒体形状过渡（雾）独立于Miro1在线粒体贩运中的作用 和DRP1诱导的线粒体裂变。尽管CA2+信号微调线粒体 生物能输出和CCA2+的持续升高驱动过多的线粒体Ca2+ 吸收是开放线粒体通透性过渡孔的先决条件 （MPTP），线粒体肿胀，质膜破裂和坏死细胞死亡。初步的 数据表明，在响应雾气，内质网（ER） - 线粒体绑定是 增加可能对MPTP的开放和线粒体反应都是必不可少的。在 对肝局部缺血再灌注损伤的反应（IRI），MPTP开放导致发作 肝坏死和随后的器官衰竭。线粒体完整性对于肝脏至关重要 IRI后的功能和生存。但是，用于的基本分子机制 线粒体完整性的维护在很大程度上是不明的。因此，我们将机械化 检查敏捷，MPTP和线粒体之间的联系，特别强调 MiRO1在MPTP形成，线粒体的启动和坏死的诱导响应 肝IRI。该项目大纲将使基本技能和专业知识的发展 需要开发PI的独立研究计划，重点是线粒体生物学 肝系统。