PHILADELPHIA - Most healthy cells rely on a complicated process to produce the fuel ATP. Knowing how ATP is produced by the cell's energy storehouse – the mitochondria -- is important for understanding a cell's normal state, as well as what happens when things go wrong, for example in cancer, cardiovascular disease, neurodegeneration, and many rare disorders of the mitochondria.
Two years ago, Kevin Foskett, PhD, professor of Physiology at the Perelman School of Medicine, University of Pennsylvania, and colleagues discovered that fundamental control of ATP is an ongoing shuttle of calcium to the mitochondria from another cell compartment. They found that mitochondria rely on this transfer to make enough ATP to support normal cell metabolism.
Now, Foskett's lab and the lab of co-corresponding author Muniswamy Madesh, PhD, at Temple University, have discovered an essential mechanism that regulates the flow of calcium into mitochondria, described in the October 26 issue of Cell. They demonstrated that the mitochondrial protein MICU1 is required to establish the proper level of calcium uptake under normal conditions.
Maintaining the correct levels of calcium in the mitochondria plays an important role in cellular physiology: Calcium flux across the inner mitochondrial membrane regulates cell energy production and activation of cell-death pathways, for example. In MICU1's absence, Madesh and Foskett found that mitochondria become overloaded with calcium, generating excessive amounts of reactive oxygen molecules and eventually cell death.
Decades in the Making
Mitochondrial calcium has been studied for nearly five decades at Penn, starting with observations made by the late Britton Chance, the Eldridge Reeves Johnson Professor Emeritus of Biochemistry and Biophysics, in the 1960s, and physiologist Tony Scarpa, in the early 1970s. Calcium uptake is driven by a voltage across the inner mitochondrial membrane and mediated by a calcium-selective ion channel called the uniporter. While the proper level of calcium influx is required for mitochondria to produce enough ATP to support cellular processes, too much influx overloads mitochondria and is toxic. Because producing ATP generates a large negative voltage that attracts the positively charged calcium ion, mitochondria face an ongoing risk of becoming overloaded with calcium.
Mitochondria somehow manage to keep the concentration of calcium in the mitochondrial matrix at beneficial levels. Remarkably, these levels are 100,000 to a million times lower than expected if calcium was simply in equilibrium with the cytoplasm. The molecular mechanisms for how this is accomplished have remained unclear.
Foskett and Madesh discovered that MICU1 interacts with the uniporter calcium channel protein MCU and sets a brake for calcium uptake by the mitochondria. This regulation is essential to prevent an overload of calcium in the mitochondria and associated cellular stress.
Until recently, the molecular identity of the uniporter was unknown. MICU1 was identified as a protein found at the inner mitochondrial membrane and seemed to be required for uniporter calcium uptake. Subsequently, MCU was identified as the likely ion-conducting part of the uniporter. MICU1 and MCU interact biochemically and their expression patterns are tightly coupled across tissues and species. Nevertheless, the relationship between them was unknown.
The Penn-Temple team found that loss of MICU1 leads to an accumulation of calcium in the mitochondria through MCU-mediated calcium uptake. Rather than being required for MCU-mediated mitochondrial calcium uptake, as previously thought, they found that MICU1 acts as the gatekeeper.
MICU senses the concentration of calcium in the matrix of the mitochondria, establishing a set point that prevents calcium uptake under normal, resting concentrations of calcium.
These findings reveal a previously unknown role for MICU1 in preventing an overload of calcium in the mitochondria. Foskett and Madesh speculate that the interaction between MICU1 and MCU may be an important site for regulating cellular bioenergetics and oxygen molecule signaling. They also suggest that disrupting the balance of the two molecules could lead to damage in neurons and cells of the heart, liver and other organs.
"Mitochondrial calcium is important for metabolic and cardiovascular functions, and maintaining this homeostasis is crucial," comments Madesh. "Cells lacking the set point will lead to mitochondrial dysfunction and cell death."
"Our findings suggest new therapeutics in a variety of pathophysiological conditions," notes first author Karthik Mallilankaraman from Temple.
"If we could discover molecules or mechanisms to impinge on the biochemical or functional interactions of MICU1 and MCU, or to modify their activities, it may be possible that metabolic dysfunctions observed in many diseases could be manipulated with beneficial therapeutic outcomes," concludes Foskett.
The research was supported by the National Institute of General Medical Science; the National Institute of Mental Health; and the National Heart, Lung, and Blood Institute (grants HL086699, HL086699-01A2S1, 1S10RR027327-01, GM56328, MH059937) as well as the American Heart Association and an NRSA Fellowship.
Other co-authors are César Cárdenas, Marioly Müller, Russell Miller, Morris J. Birnbaum, Don-on Daniel Mak, all from Penn; Karthik Mallilankaraman, Patrick Doonan, Harish C. Chandramoorthy, Nicholas E. Hoffman, Rajesh Gandhirajan, and Brad Rothberg, all from Temple; and Jordi Molgó from the Institut de Neurobiologie Alfred Fessard, Laboratoire de Neurobiolgie et Développement, France.
Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $4.3 billion enterprise.
The Perelman School of Medicine is currently ranked #2 in U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $479.3 million awarded in the 2011 fiscal year.
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