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体IV中具有最重要的作用。因此，充足的铜供应对真核生物的生存至关重要。然而，不幸的是，细胞或组织铜负荷过高与严重疾病有关，这在肝豆状核变性的发病机制中就是例证。当ATP7B酶的功能丧失时，铜从肝脏中的排出被取消，铜的积累会导致慢性活动性肝炎，甚至是伴有肝功能衰竭的重型肝炎。铜蓄积也出现在其他肝病中：慢性淤胆性肝病和非酒精性脂肪性肝病(NAFLD)患者的肝脏铜水平显著升高。这些肝病中铜蓄积的潜在原因尚不清楚，这些疾病发生和发展的致病后果也是未知的。线粒体处于铜依赖反应的中心，是铜稳态失调的第一个受害者。在最近的研究和目前的初步实验中，我们已经证明，肝豆状核变性、非酒精性脂肪肝和胆汁淤积性肝病不仅具有铜蓄积的鉴别特征，而且还具有常见的、致病性的线粒体结构和功能改变。在以前的项目中，我们已经发现了创新和高效的铜螯合剂(甲烷结合蛋白)。它们可以逆转肝豆状核变性动物模型的疾病进展，并预防肝功能衰竭。有趣的是，它们的保护作用是通过恢复线粒体功能来实现的，例如，ATP合成能力。这些结果强调了铜稳态与线粒体功能的关系。基于这些观察，我们推测铜诱导的线粒体功能损害可能是与(原发性或继发性)铜超载相关的肝病的常见致病途径。因此，当前项目的目的是为肝豆状核变性、胆汁淤积症和非酒精性脂肪肝验证这一假说。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络合剂在这些条件下应作为创新的治疗剂进行评估。具体来说，我们将：1.揭示肝脏，特别是脂肪变性和胆汁淤积中线粒体铜负荷过高的原因。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模式。

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.