Press Release

Metabolic Research

Liver's pro-survival mechanism against Wilson disease

Helmholtz Zentrum München researchers have discovered that to a certain extent, liver cells are capable of the self-digestion of cell components that have been damaged by copper. This process is called autophagy, or mitophagy when referring to damaged mitochondria. The study, which has been published in the prestigious 'Gastroenterology' journal, offers convincing evidence for the liver cells' pro-survival mechanism in Wilson disease.

Lysosome containing mitochondrial debris, isolated from deficient liver © Helmholtz Zentrum München

Wilson disease, also called hepatolenticular degeneration, is a rare hereditary defect in the metabolism of copper. In this disease, the liver is no longer able to eliminate excess copper from the body. Instead it accumulates the metal, particularly in the liver but also in other organs such as the brain, where it can cause very severe damage. Wilson disease is triggered by a defect in the so-called Wilson gene, which codes for a transport protein (ATP7B) that moves the copper out of the liver cells and into the bile. If the gene is defective, the excess copper remains in the cells and causes damage.

This constantly rising copper overload in the cell does not immediately lead to damage, however, and sometimes years pass before cell death. This suggested the possible existence of intracellular protective mechanisms. "From our previous work, we knew that the rising copper overload particularly damages the mitochondria," explains Prof. Dr. Hans Zischka, who is together with Prof. Dr. Roman S. Polishchuk last author of the study and group leader at the Helmholtz Zentrum München's Institute of Molecular Toxicology and Pharmacology (TOXI), as well as professor at the Institute of Toxicology and Environmental Hygiene at the Technische Universität München (TUM). "We wanted to investigate if there are mechanisms within the cells that can counteract such poisoning of the mitochondria in Wilson disease," Zischka continues.

The study was conducted in the framework of a joint research project involving the Helmholtz Zentrum München and the Telethon Institute of Genetics and Medicine (TIGEM), located near Naples. The scientists examined cell cultures from patients and rodent models of ATP7B deficient hepatocytes and studied their reaction to copper. "We observed that the cells use an extensive repertoire of tools to combat the copper toxicity," reports Hans Zischka. "They reacted to the addition of copper with an intensification of the mechanisms that support autophagy*." Particularly, the copper-overloaded mitochondria are affected by this process (in this case called mitophagy). When so-called autophagy inhibitors (such as Spautin-1) were deployed, the authors were able to show that cell death occurred more swiftly. Autophagy consequently helps liver cells to fight the copper toxicity that occurs in Wilson disease. During the course of the disease, this process of course helps only up to a certain level of copper overload.

The study's results now show that the potential for cell regeneration resulting from autophagy should be further investigated. This could also be interesting for other metabolic disorders that arise from the accumulation of metals. Agents that activate this pathway could reduce copper toxicity in patients with Wilson disease. However, there is no pharmacological approach known at this time.

Further information

* The term "autophagy" describes a process in which cells degrade/digest their own constituents. These can be individual proteins or even complete organelles.

Hans Zischka and his team have been investigating Wilson disease for years: In 2016 the scientists published a study that compared the new agent methanobactin to chelators that were in use in hospitals. The results for methanobactin, a bacterial substance, were very promising and are currently being investigated in further studies.

Substantially involved in the study were, from the Helmholtz Zentrum München, Mr. Josef Lichtmannegger, Ms. Claudia Einer, and doctoral student Sabine Borchard, who is participating in the PhD training program at the Helmholtz Graduate School Environmental Health, or HELENA.

Original Publication:
, EV et al. (2018): Activation of autophagy, observed in liver tissues from patients with Wilson disease and from Atp7b-deficient animals, protects hepatocytes from copper-induced apoptosis. Gastroenterology, DOI: 10.1053/j.gastro.2018.11.032

As German Research Center for Environmental Health, Helmholtz Zentrum München pursues the goal of developing personalized medical approaches for the prevention and therapy of major common diseases such as diabetes mellitus, allergies and lung diseases. To achieve this, it investigates the interaction of genetics, environmental factors and lifestyle. The Helmholtz Zentrum München has about 2,300 staff members and is headquartered in Neuherberg in the north of Munich. Helmholtz Zentrum München is a member of the Helmholtz Association, a community of 19 scientific-technical and medical-biological research centers with a total of about 37,000 staff members. 

The work of the Institute of Molecular Toxicology and Pharmacology (TOXI) focuses on elucidating the fundamental reactions of biological systems to chemical substances. The aim is to improve our understanding of the significance of such mechanisms and to gain new insights into signal networks and genetic programs responsible for the development and progression of complex diseases, such as cancer, diabetes, neurodegenerative diseases and cardiovascular disorders. Its findings form the basis for the development of improved strategies for identifying, quantifying and reducing health risks. In addition, the research promotes research into the prevention and early detection of environmental diseases and the development of innovative therapeutic approaches.

The Technical University of Munich (TUM) is one of Europe’s leading research universities, with around 550 professors, 41,000 students, and 10,000 academic and non-academic staff. Its focus areas are the engineering sciences, natural sciences, life sciences and medicine, combined with economic and social sciences. TUM acts as an entrepreneurial university that promotes talents and creates value for society. In that it profits from having strong partners in science and industry. It is represented worldwide with the TUM Asia campus in Singapore as well as offices in Beijing, Brussels, Cairo, Mumbai, San Francisco, and São Paulo. Nobel Prize winners and inventors such as Rudolf Diesel, Carl von Linde, and Rudolf Mößbauer have done research at TUM. In 2006 and 2012 it won recognition as a German "Excellence University." In international rankings, TUM regularly places among the best universities in Germany.

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