Barth syndrome is a rare congenital disease that mainly affects males, characterized by problems in mitochondrial function. It causes muscle weak point, especially in the heart, along with growth delay, and an increased risk of infection. The syndrome is triggered by an anomaly in the tafazzin gene, which interferes with the typical production of cardiolipins, vital lipids in the mitochondrial membrane.Patrick van der Wel, an associate teacher at the Zernike Institute for Advanced Materials at the University of Groningen in the Netherlands, specializes in Solid State NMR. His knowledge allows him to analyze the connections between atoms in various materials, providing insights into their structural composition.This technique is utilized to study new materials for solar panels, but also biomaterials. In a study recently published in Nature Metabolism, Van der Wel contributed to the measurements that helped discover the source of a fatal metabolic illness called Barth syndrome, which might be a step toward a cure.In Barth syndrome, something is wrong with the energy factories of the cells, the mitochondria. This causes the weakening of muscles, including the heart. As there is no known cure or treatment, clients– there are just a couple of hundred households worldwide in which this Barth syndrome is present– typically pass away prematurely.The syndrome is triggered by an anomaly in a gene called tafazzin, which produces an enzyme that contributes in the shaping of so-called cardiolipins, particles that are special to mitochondria. So far, it hasnt been clear exactly what is going wrong.This is prof. dr. Patrick van der Wel, who utilized strong state NMR to confirm the root cause of Barth syndrome. Credit: University of GroningenEnergy factoriesVan der Wel has an enduring cooperation in studying mitochondrial lipids together with scientists at the University of Pittsburgh– led by teacher Valerian Kagan– a place where Van der Wel once worked in the past. His co-workers created a hypothesis for the source of Barth syndrome: faulty cardiolipin particles would bind to a protein called cytochrome c, and form a complex that oxidizes lipids in the mitochondria.This would then damage these energy factories, causing them to malfunction. Through genetics, computer system simulations, biochemical experiments, and Van der Wels solid-state NMR measurements, the global group set out to show this scenario.Fruit flies We utilized a variety of various methods to investigate this complex, among which was solid-state NMR, says Van der Wel. This NMR technology is related to the more familiar MRI scans that are made in medical facilities. In short, this technology utilizes radio frequency signals that make atoms vibrate– a bit like striking a tuning fork. Every atom produces a distinct sound, however this is customized when they link to other atoms. This strategy reveals Van der Wel which atoms in a product are linked, and likewise what the structure of a particle is.Cardiolipin with a faulty shape makes the cytochrome c protein less rigid. This results in the formation of an oxidizing complex. Credit: Patrick van de Wel, University of GroningenIn by doing this, he had the ability to demonstrate how the defective shape of the cardiolipin could help with the formation of an oxidizing complex. A great thing about strong state NMR is that it also allows you to see the dynamics of molecules, says Van der Wel. Normally, cytochrome c is a rigid molecule, however in this complex, it ends up being floppy. This structural modification triggers the hazardous oxidation of lipids in the mitochondrial membrane. Van der Wel was able to reveal how and where a particle that improves the condition of fruit flies with Barth syndrome engages with the cytochrome c protein, an outcome that was likewise supported by the other techniques used in the study.Joint effortAs an outcome, the researchers have actually demonstrated both the likely root cause of Barth syndrome, and a potential way to treat the disease in an animal design. The roadway to a treatment for patients is still very long, but Van der Wel and his colleagues have made great progress. The next action is to evaluate the faulty complex in more detail. This would help them to, for instance, style a drug that might be used in humans.Van der Wel mentions that this research study was a genuine joint effort. Our paper is the result of the combined know-how of scientists from all over the world. Additionally, the job reveals how fundamental science can assist shed light on a really useful issue, such as the mechanism for a disease. Solid state NMR is one of the couple of approaches readily available to see what the complex of a cardiolipin with cytochrome c appears like. This suggests that our products science laboratory can provide important insights into biomedical problems. Reference: “Anomalous peroxidase activity of cytochrome c is the main pathogenic target in Barth syndrome” by Valerian E. Kagan, Yulia Y. Tyurina, Karolina Mikulska-Ruminska, Deena Damschroder, Eduardo Vieira Neto, Alessia Lasorsa, Alexander A. Kapralov, Vladimir A. Tyurin, Andrew A. Amoscato, Svetlana N. Samovich, Austin B. Souryavong, Haider H. Dar, Abu Ramim, Zhuqing Liang, Pablo Lazcano, Jiajia Ji, Michael W. Schmidtke, Kirill Kiselyov, Aybike Korkmaz, Georgy K. Vladimirov, Margarita A. Artyukhova, Pushpa Rampratap, Laura K. Cole, Ammanamanchi Niyatie, Emma-Kate Baker, Jim Peterson, Grant M. Hatch, Jeffrey Atkinson, Jerry Vockley, Bernhard Kühn, Robert Wessells, Patrick C. A. van der Wel, Ivet Bahar, Hülya Bayir and Miriam L. Greenberg, 23 November 2023, Nature Metabolism.DOI: 10.1038/ s42255-023-00926-4.
In a study recently published in Nature Metabolism, Van der Wel contributed to the measurements that helped discover the root cause of a deadly metabolic illness called Barth syndrome, which might be a step toward a cure.In Barth syndrome, something is incorrect with the energy factories of the cells, the mitochondria. So far, it hasnt been clear precisely what is going wrong.This is prof. dr. Patrick van der Wel, who utilized strong state NMR to verify the root cause of Barth syndrome. Credit: University of GroningenEnergy factoriesVan der Wel has a long-standing partnership in studying mitochondrial lipids together with scientists at the University of Pittsburgh– led by teacher Valerian Kagan– a place where Van der Wel when worked in the past. Through genetics, computer system simulations, biochemical experiments, and Van der Wels solid-state NMR measurements, the international team set out to show this scenario.Fruit flies We utilized a number of various strategies to investigate this complex, one of which was solid-state NMR, states Van der Wel. Van der Wel was able to show how and where a particle that enhances the condition of fruit flies with Barth syndrome engages with the cytochrome c protein, a result that was likewise supported by the other techniques utilized in the study.Joint effortAs an outcome, the scientists have actually demonstrated both the possible root cause of Barth syndrome, and a potential method to deal with the disease in an animal model.