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

Subject Area Gastroenterology
Term from 2018 to 2023
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 408180712
 
Final Report Year 2024

Final Report Abstract

The trace element copper is essential for the well-being of every cell in our body, especially concerning mitochondria, the cellular power plants. However, too much copper can be highly detrimental. This is best exemplified by the Morbus Wilson, characterized by impaired systemic copper excretion that can be deadly, if left untreated. Here copper accumulates in the liver, progressively impairing cellular homeostasis and especially mitochondrial function. In preparation for the here presented research work, we have demonstrated this by employing Methanobactins, a new class of copper binding chelators that reduce liver copper and restore mitochondrial structure and function. Based on these findings, we aimed at an in-depth understanding of the devastating consequences of excessive copper and the therapeutic mechanisms of Methanobactins. In addition, we aimed at unravelling a potential co-toxicity of excessive copper in fatty liver and cholestasis. Thereto this research project was structured by five key questions: Firstly, despite future work needed, concerning the mechanisms of Methanobactin restoring mitochondrial structure and function, we found that these compounds effectively eliminate liver copper via the biliary route. Intracellularly, lysosomes, the cellular recycling machinery, are involved. These organelles also degrade the copper impaired mitochondria, thereby allowing for the synthesis of highly functional, not copper burdened new mitochondria. Secondly, a high caloric diet administered to a M. Wilson animal model causes a devastating cotoxicity of fatty acids and copper characterized by massive mitochondrial damage, leading to quantitative steatohepatitis. Thirdly, such co-toxicity is also apparent in cholestasis, in which the biliary excretion of bile salts and copper are impaired. Indeed, we find such double impact on the liver that, however, was clearly ameliorated by Methanobactin high-affinity copper chelation. Fourthly, it can thus be said that too much copper not only is devastating by itself, it also severely aggravates fatty liver disease and cholestasis mostly causing necrosis. A copper reduction by Methanobactins is of therapeutic value in these diseases as well. And finally, fifthly, also based on these results, we identified one Methanobactin isoform that enabled the liver copper reduction down to healthy wild-type levels within days of treatment. None of the current clinically used drugs is able to achieve this, which is why they need to be administered lifelong, several times daily. We are therefore optimistic that the intermittent longterm treatment, shown to be effective in a M. Wilson animal model, may form the basis for the development of a much more patient-friendly therapy in this severe human disease.

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