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.