(Philadelphia, PA) – Mitochondria are the energy-generating batteries of cells, but they also perform other critical functions, including protecting cells against calcium overload, a significant cause of cell death in certain cardiovascular and neurodegenerative diseases. Underlying this safety mechanism is a protein complex known as the mitochondrial Ca2+ uniporter (MCU). New work by scientists at the Lewis Katz School of Medicine at Temple University (LKSOM) shows precisely how MCU proteins come together to effect calcium uptake, shedding new light on the physiological role of the MCU complex and its importance to cellular bioenergetics.
According to the senior investigator on the study, Muniswamy Madesh, PhD, Associate Professor in the Center for Translational Research and the Department of Medical Genetics and Molecular Biochemistry at LKSOM, how the various MCU components assemble and function as a unit has been a mystery. Knowledge of how they are brought together, however, is vital for understanding MCU activity.
"Mitochondria take up calcium in the cell through the uniporter," Dr. Madesh explained. "This process is essential for cell survival. When mitochondrial calcium uptake fails, an intracellular degradation process known as autophagy is initiated." Autophagy enables cells to balance energy sources in times of stress and is triggered by excess calcium and calcium-induced oxidative stress, factors that can also activate cell death pathways.
In the new study, published online May 12 in the journal Cell Reports, Dr. Madesh and colleagues show that MCUR1, a uniporter regulator, acts a scaffold for the MCU complex, binding to both MCU and a protein known as essential MCU regulator (EMRE). MCU and EMRE work in tandem to protect cells from calcium overload–which they could not do without the coordinating role of MCUR 1. Mice lacking MCUR1 exhibited impairments in mitochondrial calcium uptake, resulting in a mitochondrial bioenergetic crisis, in which cellular energy production was reduced. In vascular endothelial cells, the researchers were able to show that MCUR1 loss leads specifically to reduced cell migration and increased autophagy. Endothelial cell migration is necessary for the growth of new blood vessels.
"MCUR1 functions as a choreographer, bringing together the structural components of the MCU complex," Dr. Madesh explained. "This role for MCUR1 likely has important implications for improving our understanding of diseases in which mitochondrial dysfunction is a central feature."
Calcium overload and mitochondrial malfunction are major causes of cell damage sustained during heart attack and stroke, and they are significant factors in cell injury in neurodegenerative disease. Whether mutations that affect MCUR1 function are involved in the mitochondrial disruptions observed in these diseases is unknown.
Dr. Madesh and colleagues plan next to investigate the effects of small-molecule activation of MCUR1. MCU complex assembly is disrupted by mutations in MCUR1/MCU binding regions. Small molecules, however, may be able to promote MCU complex assembly despite the presence of these mutations. In theory, therapeutic applications of MCUR1 would increase calcium uptake and restore cellular energy levels.
According to Dr. Madesh, however, "Fine-tuning the level of MCUR1 activity will be key. Mitochondrial calcium uptake is essential, but inducing calcium overload in the organelles can have drastic consequences for cell function and survival."
Other researchers on the study include Dhanendra Tomar, Santhanam Shanmughapriya, Toby Thomas, Nicholas E. Hoffman, Samuel J. Goldman, Sara L. Breves, Daniel P. Corbally, Neeharika Nemani, Joseph P. Fairweather, Allison R. Cutri, Fabian J. Prado, Michael Rockman, and Sudarsan Rajan, Department of Medical Genetics and Molecular Biochemistry and the Center for Translational Medicine, Lewis Katz School of Medicine, Temple University; Diana A. Koch, Xueqian Zhang, Jianliang Song, Joseph E. Rabinowitz, Timothy S. Luongo, Sarah M. Schumacher, Joseph Y. Cheung, Walter J. Koch, and John W. Elrod, Center for Translational Medicine, Lewis Katz School of Medicine, Temple University; Alexander Dietrich, Walther-Straub-Institute for Pharmacology and Toxicology, Dr. von Hauner Children's Hospital, Comprehensive Pneumology Center, Ludwig-Maximilians-University, Helmholtz Center Munich, Munich, Germany; Shrishiv A. Timbalia and Vishal M. Gohil, Department of Biochemistry and Biophysics, Texas A&M University; Jianhe Huang, Steven R. Houser, and Vickas Patel, Cardiovascular Research Center, Departments of Medicine and Physiology, Temple University; Carlos Barrero and Salim Merali, Department of Pharmaceutical Sciences, Temple University; Jeffrey Caplan, Department of Biological Sciences, Delaware Biotechnology Institute, University of Delaware; Peter Stathopulos, Department of Physiology and Pharmacology, Western University, London, Ontario, Canada; Rexford S. Ahima, Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, Perelman School of Medicine, University of Pennsylvania; and Zhiwei Dong, Department of Medical Genetics and Molecular Biochemistry and the Center for Translational Medicine, Lewis Katz School of Medicine, Temple University, and Institute of Burn Research, Southwest Hospital, State Key Laboratory of Trauma, Burns and Combined Injury, Third Military Medical University, Chongqing, China.
The research was funded in part by the National Institutes of Health grants R01GM109882, R01HL086699, R01HL119306, 1S10RR027327, R01GM111672, and P01 DA037830.
About Temple Health
Temple University Health System (TUHS) is a $1.6 billion academic health system dedicated to providing access to quality patient care and supporting excellence in medical education and research. The Health System consists of Temple University Hospital (TUH), ranked among the "Best Hospitals" in the region by U.S. News & World Report; TUH-Episcopal Campus; TUH-Northeastern Campus; Fox Chase Cancer Center, an NCI-designated comprehensive cancer center; Jeanes Hospital, a community-based hospital offering medical, surgical and emergency services; Temple Transport Team, a ground and air-ambulance company; and Temple Physicians, Inc., a network of community-based specialty and primary-care physician practices. TUHS is affiliated with the Lewis Katz School of Medicine at Temple University.
The Lewis Katz School of Medicine (LKSOM), established in 1901, is one of the nation's leading medical schools. Each year, the School of Medicine educates approximately 840 medical students and 140 graduate students. Based on its level of funding from the National Institutes of Health, the Katz School of Medicine is the second-highest ranked medical school in Philadelphia and the third-highest in the Commonwealth of Pennsylvania. According to U.S. News & World Report, LKSOM is among the top 10 most applied-to medical schools in the nation.
Temple Health refers to the health, education and research activities carried out by the affiliates of Temple University Health System (TUHS) and by the Katz School of Medicine. TUHS neither provides nor controls the provision of health care. All health care is provided by its member organizations or independent health care providers affiliated with TUHS member organizations. Each TUHS member organization is owned and operated pursuant to its governing documents.