Researchers identifie gatekeeper protein, new details on cell's power source

October 25, 2012

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.

" is crucial for cell signaling, and keeping calcium at a certain level in the 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 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 and other activities. ATP production in turn depends on calcium, or rather, charged that can flow into the mitochondria from the cell's reservoir in the . Scientists have studied 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.

Explore further: Inhibiting CaMKII enzyme activity could lead to new therapies for heart disease

Related Stories

Inhibiting CaMKII enzyme activity could lead to new therapies for heart disease

October 11, 2012
University of Iowa researchers have previously shown that an enzyme called CaM kinase II plays a pivotal role in the death of heart cells following a heart attack or other conditions that damage or stress heart muscle. Loss ...

Cell's power generator depends on long-sought protein: 50-year search for calcium channel ends

June 19, 2011
(PhysOrg.com) -- Mitochondria, those battery-pack organelles that fuel the energy of almost every living cell, have an insatiable appetite for calcium. Whether in a dish or a living organism, the mitochondria of most organisms ...

A change of heart: Probing how chronic alcoholism alters cellular signaling of heart muscle

February 23, 2012
Beyond the personal tragedy of chronic alcoholism there is heartbreak in the biological sense, too. Scientists know severe alcoholism stresses the heart and that mitochondria, the cellular energy factories, are especially ...

Recommended for you

A sodium surprise: Engineers find unexpected result during cardiac research

July 20, 2017
Irregular heartbeat—or arrhythmia—can have sudden and often fatal consequences. A biomedical engineering team at Washington University in St. Louis examining molecular behavior in cardiac tissue recently made a surprising ...

Want to win at sports? Take a cue from these mighty mice

July 20, 2017
As student athletes hit training fields this summer to gain the competitive edge, a new study shows how the experiences of a tiny mouse can put them on the path to winning.

Engineered liver tissue expands after transplant

July 19, 2017
Many diseases, including cirrhosis and hepatitis, can lead to liver failure. More than 17,000 Americans suffering from these diseases are now waiting for liver transplants, but significantly fewer livers are available.

Lunatic Fringe gene plays key role in the renewable brain

July 19, 2017
The discovery that the brain can generate new cells - about 700 new neurons each day - has triggered investigations to uncover how this process is regulated. Researchers at Baylor College of Medicine and Jan and Dan Duncan ...

'Smart' robot technology could give stroke rehab a boost

July 19, 2017
Scientists say they have developed a "smart" robotic harness that might make it easier for people to learn to walk again after a stroke or spinal cord injury.

New animal models for hepatitis C could pave the way for a vaccine

July 19, 2017
They say that an ounce of prevention is worth a pound of cure. In the case of hepatitis C—a disease that affects nearly 71 million people worldwide, causing cirrhosis and liver cancer if left untreated—it might be worth ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.