Targeting mitochondrial dysfunction induced by copper accumulation in genetic, metabolic and cholestatic 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中发挥着最重要的作用。因此，充足的铜供应对真核生物的生存至关重要。然而，可悲的是，细胞或组织铜超载与严重疾病有关，如威尔逊病的发病机制所示。当ATP7B酶的功能丧失时，铜从肝脏的消除被取消，铜的积累导致慢性活动性甚至暴发性肝炎伴肝功能衰竭。铜积累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）患者的肝铜水平显著升高。这些肝病中铜积聚的根本原因尚不清楚，这些疾病的发病和发展的病理后果也不清楚。线粒体是铜依赖反应的中心，是铜稳态紊乱的第一个受害者。在最近的研究和目前的试点实验中，我们已经证明Wilson病，NAFLD和胆汁淤积性肝病不仅具有铜积累的区别特征，而且还以线粒体结构和功能的共同致病性改变为特征。在以前的项目中，我们已经确定了创新和高效的铜螯合剂（甲烷菌）。它们可以逆转威尔逊病动物模型的疾病进展，防止肝功能衰竭。有趣的是，它们的保护作用是通过恢复线粒体功能（如ATP合成能力）介导的。这些结果强调了铜稳态与线粒体功能的关联。基于这些观察结果，我们假设铜诱导的线粒体功能损伤可能是与（原发性或继发性）铜超载相关的肝病的常见致病途径。因此，当前项目的目的是在Wilson病、胆汁淤积病和NAFLD中验证这一假设。我们计划揭示铜稳态受损对这些肝病的发生和发展的影响，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将被评价为这些疾病的创新治疗剂。具体来说，我们将：1。揭示肝脏脂肪变性和胆汁淤积的原因，特别是线粒体铜超载。在肝豆状核变性、脂肪变性和胆汁淤积的细胞和动物模型中，对线粒体铜负荷及其对线粒体功能、细胞存活、炎症和肝功能的影响进行比较研究。在这些肝病的动物模型中测试和表征高效铜螯合剂的治疗适用性和作用方式。

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.