Metabolic cell activity directly controls life and death decisions in cells

Researchers at the University of Pennsylvania School of Medicine have found that proteins known to promote cell death are also necessary for the maturation and proliferation of immune cells.

Activation of T-cell receptors on the surface of lymphocytes by foreign antigens initiate a calcium-mediated signaling pathway that ends in cell differentiation and growth. The Penn scientists discovered that in the cells that lack the pro-death proteins Bax and Bak, calcium signaling is disrupted and energy production is reduced. Restoration of Bax corrects the signaling problems, increases energy production, and stimulates cell division.

The results, published online in the journal Immunity, bolster the team's hypothesis that metabolic cell activity directly controls life and death decisions in cells. This issue also includes a related commentary by the study's lead author, Russell Jones, PhD, and senior author Craig B. Thompson, MD.

It is well known that cells that lack Bax (Bcl-2-associated X protein) and Bak (Bcl-2-antagonist/killer) continue living under conditions that would cause normal cells to undergo programmed cell death or apoptosis. What is less well understood, is why lymphocytes missing these key proteins are unable to trigger a strong immune response and do not proliferate as normal in response to stimulation.

"We simply say they are the same thing," says Thompson, Director of the Abramson Cancer Center and Chairman and Professor of Cancer Biology and Medicine. "The molecular basis of both findings is based on how Bax and Bak work on intracellular membranes."

Specifically, the team found that when the T-cell receptor was stimulated on mutant cells lacking both proteins, proliferation was severely reduced relative to normal cells. Closer investigation showed that the amount and rate of calcium release from intracellular stores was altered in the mutant cells.

The inadequate calcium signals were unable to stimulate the mitochondria, which are the energy factories in the cell. Without mitochondrial activation, a key by-product of energy production, called reactive oxygen species or ROS, were not produced. And because ROS tell the cell to divide, cell proliferation is compromised.

Although Thompson's group investigated the function of Bax and Bak in T cells, the team thinks their findings will likely apply to many different cell types. When a cell receives signals to increase metabolism, it increases mitochondrial activity and energy production. That leads to the production of more energy than the cell can deal with, and consequently, the release of ROS. "It is the release of reactive oxygen species by the mitochondria that actually generate the proliferation. We think that is the basis of all cell proliferation," says Thompson.

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