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.

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