Lipid peroxidation as driver of cardiolipin remodeling

Mitochondria are known as the powerhouse of the cell and are built up by special lipid membranes. Their structure is crucial for efficient cellular respiration and many other functions. In order to maintain these membrane structures, the lipid building blocks have to be maintained after synthesis, since they are constantly damaged and subsequently repaired. The active repair mechanisms already play an important role under normal conditions, since membrane damage occurs continuously in mitochondria. However, they are particularly important when the chemical balance of the cells gets disturbed in conditions such as diabetes, neurodegenerative diseases including Alzheimer`s, or inherited metabolic disorders such as Barth syndrome. In this project funded by the FWF, the working group led by Dr. Markus A. Keller at the Institute of Human Genetics (Innsbruck Medical University) will investigate the contribution of these repair systems to maintaining the mitochondrial structures under different physiolo gical conditions and what measures can be taken to facilitate or accelerate the repair processes. The anticipated results are of great interest, since the composition of the lipid building blocks depends heavily on the diet. Consequently, it should be clar ified what influence the selection of the nutrients has on the susceptibility of the membranes and their repair. In addition, other active substances are tested for their influence on the membrane structure. With this project the molecular mechanisms of mitochondrial membrane repair are elucidated and quantified in detail, which will allow to conceptualize novel targeted treatment strategies to alleviate the symptoms of a number of serious diseases with impair mitochondrial membranes.

Cardiolipin is a specialized fat molecule found in cells of all living organisms and plays a central role in ensuring the functioning of our cells. It is particularly important for mitochondria-the so-called "powerhouses" of the cells that produce energy for all vital processes. Cardiolipin helps mitochondria to conduct their work efficiently by being part of the membranes of these organelles. Cardiolipin is also of particular significance in relation to Barth syndrome, a rare genetic disorder. In Barth syndrome, a mutation in a gene called TAFAZZIN causes cardiolipin to form incorrectly. This leads to severe consequences: affected individuals experience muscle weakness, growth delays, and severe heart muscle disease (cardiomyopathy), as the cells' energy supply is disrupted. Additionally, the immune system may be weakened. Both, natural and artificially induced oxidative stress can damage Cardiolipins. However, little is known about how cells cope with such damage. One possible strategy could be that cells possess a mechanism that breaks down and removes damaged Cardiolipins. Such a process was proposed several years ago. However, through this project, we were able to show that the originally suggested degradation pathway is not active in living cells and, therefore, does not contribute to Cardiolipin metabolism. Instead we found that changes in Cardiolipin in Barth syndrome also influence cell death behavior. Under highly elevated oxidative stress conditions, cells tend to follow a regulated cell death pathway known as ferroptosis. Barth syndrome cells, however, show an unusual resistance to this process. In this project, we were not only able to describe this altered behavior in detail but also propose an underlying molecular mechanism for it. Through this FWF project, we gained a deeper understanding of the interactions between Cardiolipin metabolism and cellular oxidative stress. Not only did we succeed in disproving a previously proposed hypothesis, but we also discovered a new mechanism that explains the resistance of Barth syndrome cells to oxidative stress and the ferroptosis cell death pathway. These findings open new avenues for research into oxidative stress and may, in the long term, help develop therapeutic approaches for diseases like Barth syndrome and other mitochondrial disorders.