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.

项目摘要 肝脏负责多种过程，尤其是代谢稳态和排毒。 线粒体对于肝脏的代谢功能至关重要，因此，线粒体功能障碍是主要的 肝病的原因。随着肝脏不断暴露于新陈代谢和药物的有害物质 加工，肝线粒体特别容易受到功能障碍。我们建议维护 在压力环境下的功能性线粒体将是长期保存肝脏健康的关键。 线粒体融合蛋白视乳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的重要作用，但肝脏特异性OPA1-KO小鼠仍然健康。 并保持正常的线粒体和肝功能。肝脏是具有高再生性的弹性器官 受伤后的容量。虽然OPA1-KO肝脏没有显示任何受伤，但我们发现OPA1 KO诱导了强大的 且有效的集成应力反应（ISR）来保留肝功能，表明ISR是另一种 肝脏弹性的机理。这些观察结果表明，肝脏成功处理了诱发的应力 通过OPA1 KO，提供了重要的实验系统，以机械理解ISR作为 肝脏弹性的机理。在此提案中，我们将阐明肝脏中的OPA1功能，定义 肝脏如何处理缺乏OPA1功能引起的线粒体应力的机制，并测试 利用肝脏ISR用于药物诱导的肝损伤的保护策略的可行性。我们的初步数据 表明肝脏通过临界转录的新调节具有ISR的独特机制 因子ATF4。我们还发现了OPA1作为呼吸复合物V的组装因子的新作用，并发现 复杂V的组装中间体的积累唤起了ISR诱导的线粒体应力。在 因此，这项建议将测试我们的中心假设，即OPA1是新的组装因素 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 肝脏弹性的机理。我们将通过三个特定目的检验该假设：（1）定义唯一 OPA1 KO诱导的肝脏ISR中ATF4的机制，（2）阐明OPA1作为A的新作用 复杂的V组装因子，（3）通过使用该肝脏来测试肝脏ISR作为肝脏弹性的机理 对乙酰氨基酚的过量作为药物诱导的肝损伤的模型。拟议研究的完成将 为肝脏ISR和OPA1功能的机制生成新的范式，并提供科学基础 为了制定新的治疗策略来减少肝脏疾病。