Targeting mitochondrial dysfunction induced by copper accumulation in genetic, metabolic and cholestatic hepatopathies.

针对遗传性、代谢性和胆汁淤积性肝病中铜积累引起的线粒体功能障碍。

• 批准号: 408180712
• 负责人: Privatdozent Dr. Simon Hohenester
• 金额: --
• 依托单位: Institut für Toxikologie und Umwelthygiene
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/408180712?language=en
• 关键词: Targeting; mitochondrial; dysfunction; induced; copper

Copper is an essential trace element with its most important function in the redox active complex IV of the mitochondrial respiratory chain. Adequate copper supply is thus pivotal for the survival of eukaryote organisms. Tragically, however, cellular or tissue copper overload is associated with severe disease, as exemplified in the pathogenesis of Wilson disease. When function of the enzyme ATP7B is lost, elimination of copper from the liver is abrogated and accumulating copper leads to chronic active or even fulminant hepatitis with liver failure. Copper accumulation also occurs in other liver diseases: hepatic copper levels are markedly increased in patients with chronic cholestatic liver disease and in non-alcoholic fatty liver disease (NAFLD). The underlying causes of copper accumulation in these hepatopathies are unknown, as are the pathogenetic consequences in the initiation and progression of these diseases. Mitochondria are in the center of copper-dependent reactions and are the first victims of disturbed copper homeostasis. In recent studies and in current pilot experiments, we have demonstrated that Wilson disease, NAFLD and cholestatic liver disease not only share copper accumulation as a discriminating feature but are also characterized by common, pathogenic alterations of mitochondrial structure and function.In previous projects we have identified innovative and highly efficient copper chelating agents (methanobactins). They could reverse disease progression in an animal model of Wilson disease and prevent liver failure. Interestingly, their protective effects were mediated by restoration of mitochondrial function, e.g. ATP synthesis capacity. These results underline the association of copper homeostasis and mitochondrial function.Based on these observations, we hypothesize that copper-induced impairment of mitochondrial function may be a common pathogenetic pathway in hepatopathies that are associated with (primary or secondary) copper overload. Therefore, it is the aim of the current project to test this hypothesis for Wilson disease, cholestatic disease and NAFLD. We plan to unravel the impact of impaired copper homeostasis for initiation and progression of these hepatopathies, alongside known pathogenetic factors such as genetic predisposition and environmental factors. Our recently developed, highly efficient copper chelators shall be evaluated as innovative therapeutic agents in these conditions. In detail, we will:1. Unravel the cause of hepatic, specifically mitochondrial copper overload in steatosis and cholestasis.2. Perform a comparative study of mitochondrial copper burden and the consequences for mitochondrial function, cell survival, inflammation and liver function in cell- and animal models of Wilson disease, steatosis and cholestasis.3. Test and characterize the therapeutic applicability and mode of action of highly effective copper chelators in animal models of these hepatopathies.

铜是一种必需的微量元素，在线粒体呼吸链的氧化还原活性复合物IV中具有最重要的功能。因此，充足的铜供应对于真核生物的生存至关重要。然而，不幸的是，细胞或组织铜超载与严重的疾病有关，如威尔逊病的发病机制所示。当ATP 7B酶的功能丧失时，铜从肝脏中的消除被废除，铜的积累导致慢性活动性肝炎甚至暴发性肝炎伴肝功能衰竭。铜蓄积也发生在其他肝脏疾病中：慢性胆汁淤积性肝病和非酒精性脂肪性肝病（NAFLD）患者的肝脏铜水平显着增加。这些肝病中铜积累的根本原因尚不清楚，这些疾病的发生和进展的发病后果也尚不清楚。线粒体是铜依赖反应的中心，是铜稳态失调的第一个受害者。在最近的研究和目前的试点实验中，我们已经证明，威尔逊病，NAFLD和胆汁淤积性肝病不仅共享铜积累作为一个区别特征，但也具有共同的特点，线粒体结构和功能的致病性改变。在以前的项目中，我们已经确定了创新和高效的铜螯合剂（甲烷氧化菌素）。它们可以在威尔逊病动物模型中逆转疾病进展并预防肝衰竭。有趣的是，它们的保护作用是通过恢复线粒体功能，例如ATP合成能力来介导的。这些结果强调了铜稳态和线粒体功能的关联，基于这些观察，我们假设铜诱导的线粒体功能障碍可能是与（原发性或继发性）铜超载相关的肝病的常见致病途径。因此，当前项目的目的是检验Wilson病、胆汁淤积性疾病和NAFLD的这一假设。我们计划阐明铜稳态受损对这些肝病的起始和进展的影响，以及已知的致病因素，如遗传易感性和环境因素。我们最近开发的高效铜螯合剂应作为这些条件下的创新治疗剂进行评估。具体来说，我们将：1.阐明脂肪变性和胆汁淤积中肝脏，特别是线粒体铜超载的原因.在Wilson病、脂肪变性和胆汁淤积的细胞和动物模型中进行线粒体铜负荷和线粒体功能、细胞存活、炎症和肝功能后果的比较研究。3.测试和表征高效铜螯合剂在这些肝病动物模型中的治疗适用性和作用模式。