US researchers have discovered a biological path that is essential for maintaining normal means of energy production in cells and may help us better understand metabolic processes in cancer and aging; cells use the path to shuttle calcium in and out of mitochondria, the tiny energy generators inside cells, and when it breaks down, cells consume themselves to get the energy they need.
You can read how senior author Dr J. Kevin Foskett, professor of Physiology at the University of Pennsylvania School of Medicine in Philadelphia, and colleagues, discovered how this previously unknown biological mechanism works in a paper published online in Cell on 23 July.
Humans, like many other complex organisms have eukaryotic cells comprising a membrane enclosing a nucleus and intricate networks of biological mechanisms, one of which produces energy. Energy production happens inside tiny enclosures called mitochondria, where a chemical reaction called oxidative phosphorylation combines oxygen and nutrients to produce ATP (adenosine triphosphate), the chemical that supplies cells with units of energy.
In this study, Foskett and colleagues discovered that a biological ion channel called the IP3 receptor shuttles calcium back and forth from the endoplasmic reticulum to mitochondria and that this transfer is essential for oxidative phosphorylation. (The endoplasmic reticulum is a pocket inside cells that amongst other things synthesizes proteins and regulates and stores calcium).
He and his team found that the IP3 receptor path operates at a low level all the time, and when it stops, there is not enough ATP, and cells switch to autophagy to survive, in other words they consume bits of themselves to get the energy they need.
The discovery could help us better understand not only more about how cells work, but also the biology of aging and diseases like cancer.
“Altered metabolism is a feature of many diseases, as well as aging,” Foskett told the press.
“The definition of this essential mechanism for regulating cell energy will have implications for a wide variety of physiological processes and diseases,” he added.
Using genes and chemicals, Foskett and colleagues tinkered with the way the IP3 receptor pathway releases calcium and found that the mitochondria rely on a steady level of ongoing calcium transfer to make enough ATP for normal cell metabolism, and when it stops, it triggers autophagy.
“Absence of this Ca2+ transfer results in enhanced phosphorylation of pyruvate dehydrogenase and activation of AMPK, which activates prosurvival macroautophagy,” they wrote.
They also experimented with several types of cell and found the same pattern:
“We discovered that this self consumption as a response to the lack of the calcium transfer appears to work in many types of cells, including hepatocytes from the liver, vascular smooth muscle cells, and various cultured cells lines,” said Foskett.
Autophagy is an essential housekeeping process that not only clears out rubbish but also recycles cellular products according to survival priorities: for instance in the absence of essential nutrients or energy, autophagy recycles proteins from low priority processes to fuel survival-critical processes.
There is a theory that autophagy plays an important role in either preventing or slowing down diseases such as neurdegenerative diseases, cancer and high blood pressure, although there is also a theory that it can contribute to disease.
We also know that the IP3 receptor is important for the regulation of programmed cell death, a process that gets screwed up in cancer, neurodegenerative diseases, and Huntington’s diseases.
Calcium release from the IP3 receptor could be an important insight that helps up better understand the link between how disturbance in cell metabolism affects aging, neurodegeneration and cancer, said the researchers.
Funds from the National Institute of General Medical Sciences, the National Heart, Lung, and Blood Institute, and the National Institute of Diabetes and Digestive and Kidney Diseases helped pay for the research.
“Essential Regulation of Cell Bioenergetics by Constitutive InsP3 Receptor Ca2+ Transfer to Mitochondria.”
César Cárdenas, Russell A. Miller, Ian Smith, Thi Bui, Jordi Molgó, Marioly Müller, Horia Vais, King-Ho Cheung, Jun Yang, Ian Parker, Craig B. Thompson, Morris J. Birnbaum, Kenneth R. Hallows, J. Kevin Foskett.
10.1016/j.cell.2010.06.007
Additional source: Penn Medicine.
Written by: Catharine Paddock, PhD