Mitochondrial stress in liver function and dysfunction

线粒体应激对肝功能和功能障碍的影响

• 批准号: 10909565
• 负责人: Weiqin Chen
• 金额: $ 43.89万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10909565
• 关键词: Animals; Cell Survival; Cessation of life; Chimeric Proteins; Complex; Crista ampullaris; Data; Development; Drug Metabolic Detoxication; Drug Modelings; Environment; Eukaryotic Initiation Factor-2; Exposure to; Goals; Guanosine Triphosphate Phosphohydrolases; Health; Homeostasis; Impairment; Injury; Inner mitochondrial membrane; Interruption; Knock-out; Knockout Mice; Liver; Liver Dysfunction; Liver Mitochondria; Liver diseases; Mediating; Membrane; Metabolic; Metabolism; Mitochondria; Optic atrophy 1; Organ; Oxidative Phosphorylation; Pharmaceutical Preparations; Phosphorylation; Predisposition; Process; Property; Proteins; Recovery; Regenerative capacity; Regulation; Risk; Role; Stress; Structure; System; Testing; Time; Tissues; Toxin; Translations; acetaminophen overdose; attenuation; biological adaptation to stress; design; drug induced liver injury; feasibility testing; functional disability; knockout gene; liver function; liver injury; liver preservation; mitochondrial dysfunction; novel; novel strategies; novel therapeutic intervention; oligomycin sensitivity-conferring protein; operation; preservation; prevent; protein function; resilience; respiratory; response; transcription factor

Project Summary The liver is responsible for the multitude of processes, notably the metabolic homeostasis and detoxification. Mitochondria are critical for the metabolic function of the liver and, thus, mitochondrial dysfunction is a major cause for liver diseases. As the liver is constantly exposed to harmful substances from metabolism and drug processing, liver mitochondria are especially susceptible to functional impairment. We propose that maintaining functional mitochondria under the stressful environment will be a key to the long-term preservation of liver health. The mitochondrial fusion protein optic atrophy 1 (OPA1) is essential for proper function of mitochondria, and the OPA1 gene knockout (KO) in major organs impairs mitochondrial energetics and causes animal death. However, we observed that, despite the important role of mitochondria in the liver, liver-specific OPA1-KO mice are healthy and maintain normal mitochondrial and liver functions. Liver is a resilient organ that has high regenerative capacity after injury. While OPA1-KO livers do not show any injury, we found that OPA1 KO induces a robust and efficient integrated stress response (ISR) to preserve liver function, indicating that the ISR is another mechanism of liver resiliency. These observations suggest that the liver successfully handles the stress induced by OPA1 KO, providing the important experimental system for mechanistic understanding of the ISR as the mechanism of liver resiliency. In this proposal, we will elucidate the OPA1 function in the liver, define the mechanism of how liver handles the mitochondrial stress evoked by the lack of OPA1 function, and test the feasibility of utilizing the liver ISR for a protective strategy in drug-induced liver injury. Our preliminary data indicate that the liver has a unique mechanism for ISR through a novel regulation of the critical transcription factor ATF4. We also discovered a new role of OPA1 as an assembly factor for respiratory complex V, and found that accumulation of assembly intermediates of complex V evokes mitochondrial stress for the ISR induction. In this proposal, therefore, we will test our Central Hypothesis that OPA1 is a novel assembly factor for the respiratory complex V, and its absence in the liver induces the ISR, which prevents liver injury and serves as a mechanism of the liver resiliency. We will test this hypothesis by three specific aims: (1) to define the unique mechanism regulating ATF4 in the liver ISR induced by OPA1 KO, (2) to elucidate the new role of OPA1 as a complex V assembly factor, and (3) to test the liver ISR as a mechanism of liver resiliency by using the acetaminophen overdose as a model for drug-induced liver injury. Completion of the proposed studies will generate a new paradigm for the mechanisms of the liver ISR and OPA1 function, and provide scientific basis for a new therapeutic strategy to decrease liver diseases.

项目概要 肝脏负责多种过程，特别是代谢稳态和解毒。 线粒体对肝脏的代谢功能至关重要，因此，线粒体功能障碍是肝脏代谢功能的主要障碍。 导致肝脏疾病的原因。由于肝脏不断接触代谢和药物产生的有害物质 处理过程中，肝线粒体特别容易受到功能障碍的影响。我们建议维持 压力环境下的功能性线粒体将是长期保持肝脏健康的关键。 线粒体融合蛋白视神经萎缩 1 (OPA1) 对于线粒体的正常功能至关重要，并且 主要器官中的 OPA1 基因敲除 (KO) 会损害线粒体能量并导致动物死亡。然而， 我们观察到，尽管线粒体在肝脏中发挥着重要作用，但肝脏特异性 OPA1-KO 小鼠是健康的 并维持正常的线粒体和肝脏功能。肝脏是一个有弹性的器官，具有高度的再生能力 受伤后的能力。虽然 OPA1-KO 肝脏没有表现出任何损伤，但我们发现 OPA1 KO 诱导了强大的 和有效的综合应激反应（ISR）以保护肝功能，表明 ISR 是另一个 肝脏弹性机制。这些观察结果表明肝脏成功地处理了应激引起的 由 OPA1 KO 开发，为 ISR 的机械理解提供了重要的实验系统 肝脏弹性机制。在本提案中，我们将阐明 OPA1 在肝脏中的功能，定义 肝脏如何处理 OPA1 功能缺乏引起的线粒体应激的机制，并测试 利用肝脏 ISR 作为药物性肝损伤保护策略的可行性。我们的初步数据 表明肝脏通过关键转录的新调节具有独特的 ISR 机制 因子 ATF4。我们还发现了 OPA1 作为呼吸复合物 V 组装因子的新作用，并发现 复合物 V 的组装中间体的积累会引起线粒体应激以诱导 ISR。在 因此，这个提议，我们将测试我们的中心假设，即 OPA1 是一个新的组装因子 呼吸复合物 V 及其在肝脏中的缺失会诱导 ISR，从而防止肝损伤并充当 肝脏弹性机制。我们将通过三个具体目标来检验这一假设：（1）定义独特的 OPA1 KO 诱导的肝脏 ISR 中 ATF4 的调节机制，(2) 阐明 OPA1 作为 复合体 V 组装因子，以及 (3) 通过使用 对乙酰氨基酚过量作为药物性肝损伤的模型。完成拟议的研究将 为肝脏ISR和OPA1功能机制产生新的范式，并提供科学依据 寻找减少肝脏疾病的新治疗策略。