Scientists studying mitochondrial calcium handling yield new disease targets

Dec 12, 2013

When things go wrong, cells turn to built-in safety mechanisms for survival. One of those mechanisms involves calcium uptake by mitochondria, the energy-producing powerhouses of cells. Long a mystery, new research by scientists at the Temple University School of Medicine (TUSM) Center for Translational Research shows exactly how mitochondria handle damaging excess calcium from the intracellular environment, and how problems with calcium regulation can lead to vascular damage.

"Mitochondrial calcium regulation is essential for cell survival," explained senior investigator Muniswamy Madesh, PhD, Assistant Professor in the Center for Translational Research and the Department of Biochemistry at TUSM. "But the mechanism of has been unknown."

In the late 1970s, researchers discovered a mitochondrial calcium influx "set point," a point at which become high enough in the cytoplasm (intracellular fluid) to trigger calcium uptake into mitochondria. The set point was determined to be about 3 μM. Dr. Madesh and colleagues previously discovered that below the set point, a protein now known as MICU1 works to suppress calcium influx.

Dr. Madesh's new paper, which appears this week in the journal Cell Reports, is the result of a concentrated effort to identify and describe specific interactions of MICU1. His team began by establishing a novel protein flux dynamics assay, which allowed the researchers to see where MICU1 interactions take place within mitochondria. They then introduced mutations into different regions of the MICU1 protein and investigated how the mutations affected interactions that regulate mitochondrial calcium influx.

In their protein flux experiments in cells, the team discovered that MICU1 is located in the interior region of the mitochondrion. They also identified the specific regions of MICU1 that determine binding with the uniporter that transports calcium into the mitochondrion.

To characterize the physiological relevance of MICU1, the researchers conducted experiments in mice in which MICU1 was silenced. They found that reduced MICU1 activity resulted in prolonged calcium uptake, chronic oxidative stress, and vascular dysfunction. It also diminished the ability of endothelial cells, which form the inner lining of blood vessels, to migrate, a process necessary for the formation of new blood vessels.

The new work sheds light on ways in which calcium and mitochondrial dysfunction contribute to cell and vascular damage, leading to new opportunities for the discovery of therapies capable of preventing cell injury. According to Madesh, "If we can slow down uptake and protect mitochondria, we may be able to keep mitochondrial energy levels up."

The findings have implications for other research being conducted at Temple's Center for Translational Medicine, where there is particular interest in oxidative damage sustained from conditions such as ischemic reperfusion (when blood flow resumes following a temporary pause, such as during a heart attack).

"Calcium overload and oxidative stress are implicated in cardiovascular and neurodegenerative diseases, aging, and metabolic syndrome," Madesh said. "Calcium overload and oxidative stress is a common feature in disease. It happens all the time."

Explore further: Earliest stages of ear development involve a localized signaling cascade

add to favorites email to friend print save as pdf

Related Stories

Cracking open a cell biology mystery

Aug 09, 2010

Two billion years ago somewhere in the primordial soup, one of our single-cell ancestors made a quick lunch out of another. But, in a moment of evolutionary serendipity, the would-be prey worked out a "win-win" symbiotic ...

Study may lead to new strategies against sepsis

Jan 25, 2013

Scientists at the Center for Translational Medicine at the Temple University School of Medicine are inching closer to solving a long-standing mystery in sepsis, a complex and often life-threatening condition that affects ...

Recommended for you

Genomes of malaria-carrying mosquitoes sequenced

22 hours ago

Nora Besansky, O'Hara Professor of Biological Sciences at the University of Notre Dame and a member of the University's Eck Institute for Global Health, has led an international team of scientists in sequencing ...

How calcium regulates mitochondrial carrier proteins

Nov 26, 2014

Mitochondrial carriers are a family of proteins that play the key role of transporting a chemically diverse range of molecules across the inner mitochondrial membrane. Mitochondrial aspartate/glutamate carriers are part of ...

Team conducts unprecedented analysis of microbial ecosystem

Nov 26, 2014

An international team of scientists from the Translational Genomics Research Institute (TGen) and The Luxembourg Centre for Systems Biomedicine (LCSB) have completed a first-of-its-kind microbial analysis of a biological ...

Students create microbe to weaken superbug

Nov 25, 2014

A team of undergraduate students from the University of Waterloo have designed a synthetic organism that may one day help doctors treat MRSA, an antibiotic-resistant superbug.

User comments : 0

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.