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

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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.