TOM

By studying mutations in yeast and human cells, scientists say they have found that biochemical bonds between fats and proteins in the mitochondrion, the cell's powerhouse, play a crucial role in how our cells produce energy. By studying mutations in yeast and human cells, Johns Hopkins Medicine scientists say they have found that biochemical bonds between fats and proteins in the mitochondrion, the cell's powerhouse, play a crucial role in how our cells produce energy. The study results, published June 5 in The EMBO Journal, shed new light, researchers say, on the way the altered mitochondrial membranes found in people with metabolic diseases such as Barth syndrome, a rare genetic disorder that weakens the heart, fail to enable cellular power production. Metabolism is a set of biochemical reactions central to making energy to fuel life and to getting rid of substances a body no longer needs. Metabolic diseases include forms of high cholesterol that run in families. Approximately one in three adults have some form of a metabolic syndrome, according to the National Heart, Lung, and Blood Institute. Building on previous research, the Johns Hopkins scientists sought to better understand the interaction of two components in the mitochondrial membrane: cardiolipin, a fatty compound, or lipid, and proteins that transport the building blocks of adenosine triphosphate, or ATP, an energy molecule made by the mitochondria that fuels cell metabolism. "Down the line, a better understanding of protein-lipid interactions could help researchers find new therapeutic targets for a wide range of metabolic diseases, including Barth syndrome," says senior author Steven Claypool, Ph.D., professor of physiology at the Johns Hopkins University School of Medicine. He says previous studies suggested it's likely that protein-lipid interactions in mitochondrial membranes play an important role in regulating mitochondria's powerhouse activities. The researchers conducted their experiments in samples of yeast with mutations, or alterations, in a mitochondrial membrane protein called AAC and samples of human cells that modeled a person with a mutation of the protein ANT1 who was diagnosed with metabolic disease, symptoms of which include weakness in the heart and skeletal muscles, exercise intolerance and hyperlactatemia, or elevated lactate levels in the blood. The protein in yeast, AAC, is the equivalent of ANT in humans, Claypool says. Looking at three areas where cardiolipin binds to the AAC proteins in yeast, Claypool and his colleagues found that when they introduced mutations into AAC2 to disrupt these interactions, cardiolipin could no longer bond to the protein, which weakened its structure and lowered its function. Similarly, in the cell model of the person with mutations in ANT1, the protein's structure was weakened, limiting its ability to transport ATP across the mitochondrial membrane. "These findings indicate that when the interaction between cardiolipin and proteins break down, the entire process that makes mitochondria our powerhouse is disrupted," says first author Nanami Senoo, Ph.D., a postdoctoral fellow in Claypool's lab. Claypool says few studies have detailed individual protein-lipid interactions, and many more experiments will be needed to "understand the full complement of mechanisms and roles that these interactions have in the membrane." Mitochondrial membranes contain a lot of proteins, many of which associate with lipids. "This discovery opens up new possibilities for understanding the complexities of how our cells produce energy," Claypool says. "In the future, we plan to explore how other protein-lipid interactions contribute to energy production." Other scientists who contributed to the study are Matthew G. Baile, Oluwaseun B. Ogunbona, James A. Saba, Teona Munteanu, Yllka Valdez, Kevin Whited and Macie S. Sheridan of Johns Hopkins; Dinesh K. Chinthapalli, Bodhisattwa Saha, Abraham O. Oluwole, Dror Chorev and Carol V. Robinson of University of Oxford; Vinaya K. Golla, Nathan N. Alder and Eric R. May of University of Connecticut. Funding for this study was provided by the National Institutes of Health (R01HL108882, R01HL165729, R35GM119762, T32GM007445 and T32GM136577), the American Heart Association, the Uehara Memorial Foundation, the Barth Syndrome Foundation and the Royal Society Newton International Fellowship.

A neurobiologist is pursuing important leads in her quest to elucidate the causes of neurological diseases. Together with her team, she has gained new insights into the human centrosome, whose malfunction is linked to many neurodevelopmental disorders. Internationally renowned neurobiologist Magdalena Götz is pursuing important leads in her quest to elucidate the causes of neurological diseases. Together with her team at Helmholtz Munich and Ludwig-Maximilians-Universität München, she has gained new insights into the human centrosome, whose malfunction is linked to many neurodevelopmental disorders. The centrosome is the organelle responsible for the organization of the cytoskeleton during cell division, an essential function in organisms from yeast to humans. Until now, scientists assumed that the centrosome was very similar in all cells due to its general tasks. However, Magdalena Götz and her team evaluated this notion in neurons and their developmental precursors, so-called neuronal stem cells. "There is so much we don't yet know about these cells, including how the centrosomes of neurons compare to those of neural stem cells and other cell types," Götz says. Their subsequent discoveries now fundamentally challenge the assumption that all centrosomes are created equal. Centrosomes are in fact not "one type fits all" In close collaboration with the Helmholtz Munich Proteomic Core Facility led by Stefanie Hauck, the researchers found that the composition of proteins in centrosomes differs profoundly depending on the cell type. "We were surprised not only by the unexpected high degree of heterogeneity of the centrosomes, but also by the discovery of many unexpected proteins associated with them -- for example, RNA-binding proteins and even proteins responsible for splicing (the processing of RNA), which normally takes place in the nucleus," Götz explains: The location of centrosome-associated proteins is crucial for disease The scientists discovered that a specific protein (the ubiquitously expressed splicing protein PRPF6) is enriched at the centrosome in neural stem cells, but not in neurons. A mutation of the protein found in patients with brain malformation periventricular heterotopia also leads to a similar phenotype in animal models. Magdalena Götz concludes, "This means that the location of a protein is crucial for a disease. With our centrosome analysis, we now have an important resource to test further associations with neuronal diseases. In particular, our research can explain for the first time why a protein that is present in all cells, after mutation, causes a phenotype only in the brain, but not in other organs. This will allow further insights into disease mechanisms -- and thus get one step closer to their treatment." About the people Professor Magdalena Götz is a director at Helmholtz Munich since 2004, where she heads the Institute of Stem Cell Research. She also holds the Chair of Physiological Genomics at Ludwig-Maximilians-Universität München. In 2019, she received the Mendel Medal of the National Academy of Sciences Leopoldina for her scientific achievements. She conducted the current study together with first authors Adam C. O'Neill, Fatma Uzbas, Giulia Antognolli and Florencia Merino, among others.