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.

抽象的： 在细胞系统中，线粒体形成了一个由相互连接的线粒体组成的复杂网络。 不同的形状和尺寸。线粒体与其他细胞器形成紧密联系 这对于维持线粒体的完整性和功能至关重要。新兴 有证据表明线粒体结构和参与过程的复杂性 维持细胞内功能性线粒体库。线粒体结构是 受各种病理生理信号的调节，如营养可用性、激素调节、 以及调节胞质钙 (cCa2+) 动态的应激条件。动态 cCa2+ 的变化通过 Ca2+ 感应线粒体外层调节线粒体形状 膜锚定的 EF-hand 含有蛋白质 Miro1。这种现象被称为 线粒体形状转变 (MiST) 与 Miro1 在线粒体运输中的作用无关 和 Drp1 诱导的线粒体裂变。尽管 Ca2+ 信号可以微调线粒体 生物能输出和 cCa2+ 持续升高导致线粒体 Ca2+ 过量 摄取是线粒体通透性转换孔打开的先决条件 (MPTP)、线粒体肿胀、质膜破裂和坏死细胞死亡。初步的 数据表明，响应 MiST，内质网 (ER)-线粒体束缚 增加，这对于 MPTP 开放和线粒体自噬反应可能都是必需的。在 对肝缺血再灌注损伤（IRI）的反应，MPTP开放导致肝缺血再灌注损伤（IRI）的发生 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 后的功能和存活率。然而，其潜在的分子机制 线粒体完整性的维持在很大程度上尚不清楚。因此，我们会机械地 检查 MiST、MPTP 和线粒体自噬之间的联系，特别强调 Miro1 在 MPTP 形成、线粒体自噬的启动以及响应于 肝脏IRI。项目大纲将促进基本技能和专业知识的发展 需要开发 PI 的独立研究项目，重点关注线粒体生物学 肝脏系统。