Temple-Penn team identifies gatekeeper protein, new details on cell's power source

New insights may eventually lead to therapies against a range of diseases

2012-10-25

(Press-News.org) (Philadelphia, PA) – Researchers at Temple University's Center for Translational Medicine and the University of Pennsylvania have identified a protein that serves as a gatekeeper for controlling the rush of calcium into the cell's power source, the mitochondria. Without this calcium spigot under control, calcium levels can run amok, contributing to cardiovascular disease, diabetes and neurodegeneration. The findings, reported online October 25, 2012, in the journal Cell, add important new insights into the inner workings of the mitochondria and may eventually help scientists better understand and target certain cellular processes gone awry, leading to new therapies for disease.

"Calcium is crucial for cell signaling, and keeping calcium at a certain level in the mitochondria is important to help regulate various cell processes and physiology," said co-senior author Muniswamy Madesh, PhD, Assistant Professor of Biochemistry at Temple University School of Medicine and a member of Temple's Center for Translational Medicine. "We've shown this gatekeeper establishes a threshold for calcium and prevents it from rushing in and overwhelming the mitochondria, which if unregulated, can act as a sponge and soak up large amounts of calcium in the cell. These results may help us find new ways to control calcium levels and head off problems that might lead to disease."

Maintaining a proper level of calcium is imperative for cells to work properly, and is particularly important in the mitochondria. Cells rely on mitochondria to generate usable energy sources in the form of the chemical ATP, which is necessary to carry out normal cellular metabolism and other activities. ATP production in turn depends on calcium, or rather, charged calcium ions that can flow into the mitochondria from the cell's reservoir in the cytoplasm. Scientists have studied calcium uptake by mitochondria for some five decades, but the details of the mechanisms for managing it under normal conditions were unclear.

Dr. Madesh, co-senior author Kevin Foskett, PhD, at the University of Pennsylvania, and their co-workers may have at least in part solved this mystery. They found a molecular mechanism – a mitochondrial "gatekeeper" protein called MICU1 – that guards a protein pore, controlling how much calcium comes into the mitochondria. The researchers found that MICU1 works with this calcium channel pore, MCU, to set a threshold for the amount of calcium coming into the mitochondria specifically to enable the cell to maintain a level of calcium in mitochondria under normal "resting conditions."

Using a technique to silence gene and protein expression, the researchers found that when they turned off MICU1, excess cellular calcium was rapidly taken up by the mitochondria. When they re-expressed the molecule, they found that once again the calcium influx was under control. MICU1 detected calcium in the surrounding mitochondrial matrix at a certain level, maintaining comparatively low levels of mitochondrial calcium – about five to six times lower than what is considered "equilibrium."

"This gave us a clue that maybe there is a threshold at which mitochondria sense cellular calcium, and this protein acts like a sensor," Dr. Madesh noted.

"We've shown that the MICU1 establishes and controls a set point, which is crucial to maintaining the cell's calcium homeostasis," Dr. Madesh said. "Mitochondria in healthy cells rely on this mechanism to protect from calcium overload under physiological conditions. Disrupting this gatekeeper and the set point and chronically elevating mitochondrial calcium could lead to damage in neurons, and in the heart, liver, and other organs. Mitochondrial calcium is important for metabolic and cardiovascular functions, and maintaining this homeostasis is crucial. Cells lacking the set point will lead to mitochondrial dysfunction and cell death."

The findings suggest an array of potential therapeutic options to explore, including gene therapy, said first author Karthik Mallilankaraman, PhD, a postdoctoral fellow in the Department of Biochemistry and the Center for Translational Medicine at Temple University School of Medicine.

### Other researchers contributing to the work include Patrick Doonan, Harish C. Chandramoorthy, Nicholas E. Hoffman, Rajesh Gandhirajan, and Brad Rothberg, Temple University, Cesar Cardenas, Marioly Muller, Russell Miller, Morris J. Birnbaum, Don-on Daniel Mak, University of Pennsylvania, and Jordi Molgo, Institute de Neurobiologie Alfred Fessard, Laboratoire de Neurobiolgie Cellulaire et Moleculaire, France.

The work was supported by funding from the National Institutes of Health and the American Heart Association.

About Temple Health

Temple Health refers to the health, education and research activities carried out by the affiliates of Temple University Health System and by Temple University School of Medicine.

Temple University Health System (TUHS) is a $1.4 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 Temple University School of Medicine.

Temple University School of Medicine (TUSM), established in 1901, is one of the nation's leading medical schools. Each year, the School of Medicine educates approximately 720 medical students and 140 graduate students. Based on its level of funding from the National Institutes of Health, Temple University 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, TUSM is among the top 10 most applied-to medical schools in the nation.

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Temple-Penn team identifies gatekeeper protein, new details on cell's power source

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