East Montgomery Times

Calcium transport into mitochondria is crucial to energy production and cell survival, and researchers at Lewis Katz School of Medicine at Temple University have shed light on a pivotal protein in this process. 'TMEM65' is the newly identified molecule that regulates the mitochondrial sodium-calcium exchanger (NCLX), playing a critical role in moving calcium out of mitochondria and protecting cells from damage due to calcium overload.

The study, available online since April 8 in 'Nature Metabolism', marks the first instance where the interaction of TMEM65 with NCLX in mitochondria has been characterized. "TMEM65 is the first protein identified that is a bona fide interactor and regulator of NCLX," stated John W. Elrod, PhD, senior investigator and Chair in Cardiovascular Medicine at the Lewis Katz School. The insights from this discovery offer scientists potential pathways to design therapeutic agents targeting conditions such as heart failure and Alzheimer's disease.

Investigating mitochondrial calcium exchange is vital since excess calcium intake disrupts energy metabolism and cell viability, particularly impacting the heart during heart failure and brain cells in neurodegenerative diseases like Alzheimer's. Dr. Elrod previously recognized NCLX's importance in removing mitochondrial calcium and suggested that enhancing NCLX could mitigate heart failure, Alzheimer's progression, and potentially cancer. However, the mechanisms moderating NCLX have not been fully understood until now.

"NCLX has a very complex structure, which has impeded the study of its regulation," Elrod said. For their recent study, he and his team used biotin tagging to trace interactions of NCLX with other proteins. By implementing this method, researchers discovered that TMEM65 notably regulates NCLX function when calcium levels escalate in mitochondria.

"TMEM65 was of particular interest because it is a mitochondrial protein of unknown function," Elrod explained, citing a medical case involving a girl with compromised TMEM65 that resulted in severe muscle weakness and brain abnormalities. When TMEM65 was removed in experiments, mitochondrial calcium increased, confirming its role in NCLX regulation. This was further verified in a mouse model of TMEM65 deficiency, which displayed impaired neuromuscular function.

The research efforts broadening the understanding of TMEM65 have been acknowledged in the scientific community. Joanne F. Garbincius, PhD, Elrod’s postdoctoral fellow, received the prestigious American Heart Association's Louis N. and Arnold M. Katz Basic Science Research Prize in 2024 for this groundbreaking work.

Research continues as Dr. Elrod and his team explore manipulating TMEM65 activity therapeutically. "TMEM65 is a promising therapeutic target," added Dr. Elrod. "Figuring out how to augment or otherwise alter its interaction with NCLX could offer an important treatment option for patients affected by diseases involving pathogenic calcium buildup in mitochondria."

Amy J. Goldberg, MD, FACS, the Marjorie Joy Katz Dean at the Lewis Katz School, emphasized the study's importance, "This discovery exemplifies the transformative science happening at the Lewis Katz School of Medicine."

Contributors to the study include Oniel Salik, Henry M. Cohen, Carmen Choya-Foces, and others from Lewis Katz School and Dhanendra Tomar from Wake Forest University School of Medicine. The research received support from the National Institutes of Health and the American Heart Association.