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 肝脏负责许多过程，特别是代谢动态平衡和解毒。 线粒体对肝脏的新陈代谢功能至关重要，因此，线粒体功能障碍是主要的 导致肝病的原因。因为肝脏经常暴露在代谢和药物的有害物质中 在加工过程中，肝脏线粒体特别容易受到功能损伤的影响。我们建议保持 应激环境下的功能性线粒体将是长期保存肝脏健康的关键。 线粒体融合蛋白视神经萎缩1(OPA1)是线粒体正常功能所必需的，而 OPA1基因敲除(KO)在主要器官损伤线粒体能量学，导致动物死亡。然而， 我们观察到，尽管线粒体在肝脏中起着重要作用，但肝脏特异的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，具有高度的再生性。 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)来保护肝功能，表明ISR是另一种 肝脏回弹的机制。这些观察表明，肝脏成功地处理了由 由OPA1 KO提出，为从机理上理解ISR提供了重要的实验系统 肝脏回弹的机制。在这个提案中，我们将阐明OPA1在肝脏中的功能，定义 肝脏如何处理由OPA1功能缺失引起的线粒体应激，并测试 利用肝脏ISR作为药物性肝损伤的保护策略的可行性。我们的初步数据 提示肝脏通过一种新的关键转录调控机制对ISR具有独特的作用机制 因子ATF4。我们还发现了OPA1作为呼吸复合体V的组装因子的新作用，并发现 复合体V的组装中间产物的积累引起线粒体应激，以诱导ISR。在……里面 因此，这一提议将检验我们的中心假设，即OPA1是一种新的 呼吸复合体V及其在肝脏中的缺失可诱导ISR，从而防止肝脏损伤，并作为一种 肝脏回弹的机制。我们将通过三个具体目标来检验这一假设：(1)定义唯一的 OPA1 KO诱导的肝脏ISR中ATF4的调节机制，(2)阐明OPA1作为一种新的 复杂的V装配因子，和(3)测试肝脏ISR作为肝脏弹性的机制 醋氨酚过量作为药物性肝损伤模型的研究。建议的研究完成后， 为肝脏ISR和OPA1功能的机制建立新的范式，并提供科学依据 寻找一种新的治疗策略来减少肝脏疾病。