Programmed cell death may provide clues to cancer and autoimmune diseases therapies

Dartmouth Medical School geneticists have found links in the cell death machinery of worms and mammals, opening new avenues for studying and targeting a process vital to development and implicated in cancer and autoimmune diseases.

The work, reported in the February 17 issue of Nature, demonstrates the role of mitochondria, the cellular power plant, in prompting worm cells to self destruct. These results unify cell death models along the evolutionary spectrum, from simple animal systems to humans.

In spite of its name, programmed cell death, or apoptosis, is essential for life; it's needed for nervous system development and it keeps the body up and running. Miscues and failures are instrumental in cancer, autoimmune disorders or neurodegenerative diseases.

Mitochondria, the organelles responsible for producing energy to fuel cell processes, also appear to release molecules that set the cell death program in motion. While their activity in mammalian cell death was known, mitochondrial involvement in worms had not previously been shown.

The new work, led by Dr. Barbara Conradt, assistant professor of genetics at Dartmouth Medical School, reveals the importance of mitochondria in cell death in the roundworm C. elegans, enhancing the view of how cell death is conserved from worms to humans.

"Now it seems that there is really one way of killing cells and it involves these mitochondria. Using genetics, we could rigorously show that mitochondria are part of it. It unifies two different hypothesis and makes worms a great model to analyze how cell death is induced, " Conradt said.

Mitochondria are dynamic structures, constantly changing shape, budding and fusing. In cells instructed to die, the mitochondria tend to become smaller or fragment, but whether this fragmentation is a requirement for cell death or a byproduct has been unclear, until now.

Conradt and her colleagues determined that mitochondrial fragmentation is required for cells to die and that the process that commits cells to the point of no return happens quickly. Conradt said it's the clearest confirmation yet that mitochondrial fragmentation is critical in killing cells.

C. elegans worms are a convenient model system, Conradt explained, with a well documented cell lineage that facilitates genetic manipulation. Their cell death machinery is simple, with one component for each of the different factors involved in the central cell killing apparatus. Mammals on the other hand have multiple components or families of proteins for these factors; moreover, their cell death is more sporadic and harder to pinpoint.

In worms, scientists know exactly which cells are dying, and when and where. During development, 1,090 cells form, but 131 of these cells die; the same cells always die at the same time and at the same place. This feature makes it possible to identify mutant worms, in which cells that should have died instead live. Worms whose cell death program is blocked survive, at least in the lab, with their 131 extra cells. Such studies are impractical in mammals because cell death is essential and animals with a cell death defect die.

The researchers demonstrated that when they cause worm mitochondria to fragment without instructing cells to die, the cells still die and when they block fragmentation, the cells survive; in other words, blocking fragmentation prevents cell death, inducing fragmentation provokes cell death.

"This programmed cell death is so important and the more players we know that are involved, the more potential targets we have for therapeutics," Conradt said. During development, for example, many neurons are built, but after birth, more than half are eliminated in the central nervous system in mammals: "It's a common safeguard, to ensure that neurons talk to the right neighbors and make the right connections." Also, if cells do not die on schedule, unregulated growth can lead to tumors and other complications.

"Mammalian studies that have implicated mitochondrial fragmentation in cell death have been done under rather artificial conditions, in tissue culture, not using natural cell death stimuli, " Conradt explains. "Our work was done in vivo; in the worm. We looked at cells that normally die, so it's more solid."