ATP Keeps it Running
Adenosine-5'-triphosphate (ATP) is a nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism. 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 discovered that fundamental control of ATP production 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.
Foskett’s lab and the lab of colleague Muniswamy Madesh, PhD, at Temple University, discovered last month an essential mechanism that regulates the flow of calcium into mitochondria, described in the October 26 issue of Cell. They found that the mitochondrial protein MICU1 is required to establish the proper level of calcium uptake under normal conditions.
By painstakingly shutting down the activity of 50 genes, one at a time, they have identified a protein, MCUR1, which hugs the inside of the mitochondrial membrane and is part of an elaborate mitochondrial channel pore system. MCUR1 acts as an accelerator to help regulate calcium coming into the mitochondria from the cell's large reservoir.
Like MICU1, this new protein, MCUR1, interacts physically with MCU, the uniporter calcium ion channel within the mitochondria. Calcium uptake is driven by a voltage across the inner mitochondrial membrane and mediated by the calcium-selective ion channel called the uniporter.
"But this newly described protein, MCUR1, has the opposite role as MICU1," notes Foskett. "It seems to be a subunit that, together with MCU, is required for a functional uniporter calcium channel." An uniporter is a channel protein that transfers only one substrate at a time across the membrane.
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 mitochondria become overloaded with calcium, generating excessive amounts of reactive oxygen molecules and eventually cell death. In contrast, in the absence of MCUR1, mitochondria cannot take up enough calcium. This also has detrimental effects: the cells cannot make enough ATP and they activate autophagy, a mechanism in which cells eat themselves to provide sufficient nutrients for survival
Because of these two papers, the uniporter is now recognized as a channel complex, containing -- at least -- MCU, MCUR1 and MICU1. Since the uniporter can be a therapeutic target is reperfusion injury, ischemic injury, and programmed cell death, MCUR1 and its interaction with MCU are now targets for drug development.
Dr. Madesh explained that in some disease conditions — such as ischemic reperfusion injury (tissue damage that occurs when blood returns to tissue after a period without oxygen), stroke involving brain injury from ischemia, and myocardial infarction — calcium floods into the mitochondria. "The mitochondria have a massive membrane potential and grab external calcium. The mitochondria then are overloaded and rupture, leading to cell death and possible organ injury."
Because some diseases are characterized by an overabundance of calcium in the mitochondria, a possible therapy could involve slowing down the amount of calcium coming into the mitochondria. "We want to control the calcium entering the mitochondria," he said.
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Ca2+ flux image created by Lili Guo, Perelman School of Medicine, University of Pennsylvania.