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: 10803227
• 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/10803227
• 关键词: Ablation; Architecture; Automobile Driving; Autophagosome; 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; Link; Lipids; Liver; Maintenance; Mediating; Membrane; Membrane Potentials; Membrane Proteins; Metabolism; Mitochondria; Mitochondrial Swelling; Molecular; Mus; Mutation; Necrosis; Necrosis Induction; Nutrient availability; 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; 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.

摘要： 在细胞系统中，线粒体形成了一个复杂的相互连接的线粒体网络， 不同的形状和大小。线粒体与其他细胞器形成密切联系 其对于维持线粒体完整性以及功能是必需的。新兴 有证据表明，线粒体结构和过程的复杂性， 维持细胞内功能性线粒体库。线粒体结构是 由各种病理生理信号调节，如营养可用性，激素调节， 以及调节细胞溶质钙（cCa 2+）动力学的应激条件。动态 cCa 2+的变化通过Ca 2+敏感的线粒体外膜调节线粒体的形状。 膜锚定EF-手含有蛋白质Miro 1。这种现象被称为 线粒体形状转变（MiST）与Miro 1在线粒体运输中的作用无关 和Drp 1诱导的线粒体分裂。虽然Ca 2+信号微调线粒体 生物能量输出，cCa 2+的持续升高驱动过多的线粒体Ca 2 + 这是线粒体通透性转换孔开放的先决条件 （MPTP）、线粒体肿胀、质膜破裂和坏死细胞死亡。初步 数据表明，作为对MiST的反应，内质网（ER）-线粒体系留被 增加，这可能对于MPTP开放和有丝分裂反应至关重要。在 在对肝缺血再灌注损伤（IRI）的反应中，MPTP开放导致肝缺血再灌注损伤（IRI）的发生。 肝坏死和随后器官衰竭。线粒体的完整性对肝脏至关重要 IRI后的功能和存活率。然而，潜在的分子机制， 线粒体完整性的维持在很大程度上是未确定的。因此，我们将机械地 检查MiST，MPTP和线粒体自噬之间的联系，特别强调 Miro 1在MPTP形成、线粒体自噬启动和诱导坏死中的作用 肝IRI。项目纲要将有助于发展基本技能和专门知识 需要发展PI的独立研究计划，重点是线粒体生物学， 肝脏系统。