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The transport of calcium in and out of mitochondria, often referred to as the powerhouses of cells, plays a critical role in both energy production and programmed cell death. A protein known as the mitochondrial sodium-calcium exchanger (NCLX) is essential for regulating calcium balance within these organelles. Recent studies from the Lewis Katz School of Medicine at Temple University have unveiled a new regulator of NCLX, a protein named TMEM65, which facilitates the export of calcium from mitochondria and helps prevent calcium overload.
This significant finding was published on April 8 in the journal Nature Metabolism and marks the first detailed examination of how TMEM65 interacts with NCLX in mitochondria. Dr. John W. Elrod, a leading researcher in the study, noted that TMEM65 is the first identified protein that directly interacts with and regulates NCLX. This discovery could pave the way for the development of novel therapeutic options to address mitochondrial calcium overload in conditions like heart failure and Alzheimer’s disease.
The exchange of calcium within mitochondria is vital for maintaining cell survival and activating energy-related signaling pathways. Excessive calcium uptake can lead to disrupted energy metabolism and cellular death, which is particularly detrimental in the heart, where cell death from calcium overload can be irreversible following heart attacks or during heart failure. Similarly, neurodegenerative diseases such as Alzheimer’s can result from similar mechanisms leading to the degeneration of brain cells.
Previously, Dr. Elrod’s team had pinpointed NCLX as crucial for calcium elimination from mitochondria in both the heart and the brain. Their research indicated that enhancing NCLX function could slow down the progression of heart failure, Alzheimer’s, and even some cancers. However, the regulatory mechanisms governing NCLX remain poorly understood.
“The intricate structure of NCLX has made studying its regulation quite challenging, which has slowed down therapeutic advancements,” explained Dr. Elrod. “To address this, we adopted a biotin tagging technique that enabled us to monitor NCLX’s interactions within living cells.”
Under the direction of postdoctoral fellow Dr. Joanne F. Garbincius, the research team developed a fusion between NCLX and a biotinylation protein, which was then introduced back into cells. Nearby proteins were labeled biochemically, allowing for their subsequent isolation and identification through mass spectrometry. This innovative approach led to the identification of TMEM65 as a key regulatory protein of NCLX.
Dr. Elrod emphasized the particular interest in TMEM65, as it is a mitochondrial protein with an unclear function. The relevance of TMEM65 was underscored by a case report describing a young girl with a mutation in TMEM65, who exhibited severe muscle weakness as well as microcephaly and neurological complications.
Further investigations indicated that the absence of TMEM65 in cells resulted in excessive calcium accumulation within mitochondria, confirming TMEM65’s necessity for NCLX functionality. In mouse models lacking TMEM65, researchers observed a gradual decline in neuromuscular coordination, resulting in significant mobility impairment by adulthood.
The methodologies employed to discover TMEM65 and analyze NCLX regulation are considered groundbreaking in cardiovascular research. In acknowledgment of her contributions, Dr. Garbincius received the Louis N. and Arnold M. Katz Basic Science Research Prize for Early Career Investigators from the American Heart Association in 2024.
The findings have spurred further examinations into the role of TMEM65. Dr. Elrod and his team plan to investigate the potential of modifying TMEM65 activity as a possible treatment strategy. “TMEM65 presents an attractive target for therapy,” he stated. “Understanding how to enhance or alter its interaction with NCLX may lead to viable treatment options for patients affected by diseases linked to abnormal calcium accumulation in mitochondria.”
Dr. Amy J. Goldberg, Dean of the Lewis Katz School of Medicine, highlighted the importance of this research, stating, “This breakthrough showcases the transformative scientific work being conducted here at the Lewis Katz School of Medicine. By deepening our insights into mitochondrial dynamics, our team is laying the groundwork for innovative therapies that could significantly benefit patients suffering from heart failure, Alzheimer’s disease, and other related conditions.”
The study featured contributions from numerous researchers, including Oniel Salik, Henry M. Cohen, Carmen Choya-Foces, and others from the Aging + Cardiovascular Discovery Center, as well as Dhanendra Tomar from Wake Forest University School of Medicine. Funding for the research was provided in part by the National Institutes of Health and the American Heart Association.
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