The ’upstairs/downstairs’ mystery of cell suicide is burdened by too much evidence

Researchers know that the many different roads to cell suicide all run through mitochondria, but do not know which roads are the ones most traveled by the signals that signify death

The story of how mitochondria are recruited during times of stress to choreograph apoptosis–the cell’s dance of death–is a story that fails to tell which particular set of steps the cells use most often, according to investigators at St. Jude Children’s Research Hospital and the La Jolla Institute of Allergy and Immunology (San Diego, CA).
Mitochondria are sacs of enzymes in the cell that extract energy from food and store this energy in the high-powered chemical bonds of molecules called ATP. Virtually all activity of cells requires energy supplied by ATP, which acts as the “currency” with which the cell “buys” chemical reactions.

The fact that more than 100,000 research papers on apoptosis have been published is ironic, since this vast amount of information contributes to the confusion over which signaling pathways are most important for triggering this process, according to Douglas R. Green, Ph.D., chair of Immunology at St. Jude and holder of the Peter C. Doherty Endowed Chair of Immunology. Green is senior author of an editorial on apoptosis that appears in the October 7 issue of Science.

Apoptosis is the orderly process that both sculpts developing organisms out of a mass of replicating cells and disposes of irreparably damaged, mutated or infected cells. For example, cells that suffer DNA mutations that cannot be repaired undergo apoptosis to prevent them from forming a tumor.

Understanding the fine points of apoptosis is important to researchers seeking ways to control this process, Green said. Among the many therapeutic applications of such control would be triggering cancer cells to commit suicide. “But we can’t design definitive treatments until we understand which pathways leading to apoptosis are the most important,” Green said.

The major event in apoptosis is the breakdown of the membranes of the mitochondria. This breakdown allows certain proteins to spill out of the mitochondrion and help form a suicide switch called the apoptosome. Some of the critical steps in apoptosis occur before that breakdown of the mitochondria, that is, “upstairs” from the mitochondria, Green said. The other critical steps occur after, or “downstairs” from the mitochondria, he added.

“Based on all the information available, you could conclude that an enormous number of molecules and pathways trigger apoptosis,” Green noted. “So we need to identify the most important series of steps in this process. Otherwise we might concentrate too much of our attention on relatively unimportant byways on the road to apoptosis and miss the major highways.”