Structural analysis of a pathogenic protein-lipin complex in Barth syndrome

Patrick van der Wel, PhD, University of Groningen

2024 Development Award, $75,000 over two and a half years

Barth syndrome (BTHS) is caused by a defect in an enzyme called TAFAZZIN, that is responsible for making mature lipid (e.g. fat) molecules in mitochondria. Mitochondrial lipids in healthy cells form a structure called a membrane, which surround these cellular powerhouses (energy production), making them work. In addition to this role, these membranes also serve as a barrier to protect the rest of the cell from potentially dangerous chemicals generated during cellular power generation. In Barth syndrome, however, defective lipids reduce the stability of these vital membranes. The breakdown of these cellular barriers plays an important role in Barth syndrome, making this a potentially interesting target for future therapies. To direct drug development towards this new area of understanding, we first need to understand what goes wrong at a molecular level. In this project, we will use advanced experimental techniques to visualize these abnormal processes. Planned experiments are based on a technique similar to an MRI scan but at a molecular level. Our team will use this approach to see how the different players (proteins, lipids, potential drugs) interact with each other. In earlier work, we used these molecular scans to see how relevant proteins and lipids form a complex only when TAFAZZIN is mutated. These complexes are dangerous to the cell but are hard to visualize. Now, we will further develop our understanding of what they look like and how their presence affects the integrity of mitochondrial membrane barriers. We will also study the way that these dangerous processes are affected by a potential drug molecule that was previously found to have benefits in animals used to model Barth syndrome. Thus, we will gain an understanding on the microscopic and even molecular level of how drug-like molecules change the dysfunctional events. We hope that this information will help us better understand what goes wrong in Barth syndrome and yield insights into how molecules can be designed to correct these disease-causing processes.

This co-funded project was made possible by a generous contribution from our affiliate Association Syndrome de Barth France.