Sci. Aging Knowl. Environ., 18 August 2004
Membranes of Death
Molecule prevents suicide triggered by cell's protein factories
When the going gets tough, many cells give up. But some endure if they've got a protein that prevents a particular organelle from sparking cell suicide, new work suggests. The results might eventually help researchers identify ways to curtail cell loss associated with Alzheimer's disease and stroke.
Several routes can lead to cell suicide, or apoptosis. The tumor necrosis factor (TNF) pathway rouses enzymes called caspases that incite death. Mitochondria also help determine a cell's fate. When damaged by oxidants or other stresses, these organelles spill their guts, lose their electrical charge, and activate caspases. Another cell component can trigger apoptosis too--the endoplasmic reticulum (ER). Leaking calcium and misshapen proteins unleash the ER's suicidal urgings, which might contribute to brain damage from stroke as well as Alzheimer's and Parkinson's diseases. Moreover, recent work indicates that communication between the ER and mitochondria helps govern cell suicide. In what seemed like an unrelated discovery, molecular biologist John Reed of the Burnham Institute in La Jolla, California, and a colleague showed in 1998 that an ER protein called BI-1 squelched apoptosis in yeast. Further study revealed that the plant version of BI-1 spares human cells. Reed and colleagues wanted to find out whether BI-1 from mammals was also protective.
The researchers cultured connective tissue cells from mice that lack the gene for BI-1. When they added chemicals that provoke the TNF and mitochondrial suicide pathways, control and altered cells were equally vulnerable. But when they mixed in compounds that stress the ER, more cells missing BI-1 died. Additional studies suggested that BI-1 shields brain and liver cells from ER-provoked death. Next, the team injected an ER-irritating compound into adult mice lacking BI-1. Lesions composed of dead and wounded cells sprouted in their kidneys and brains, whereas control rodents were unscathed. To determine whether BI-1 might guard against stroke, the researchers temporarily cut off blood flow to part of the brain. Mice without BI-1 carried larger scars than did controls.
The team then tested cells that pumped out extra BI-1. These cells survived compounds that were particularly effective at provoking ER stress. The ER appeared marred, but the mitochondria remained sound and caspase activity was scant. Further experiments indicated that when the altered cells were under duress, the ER spilled unusually small amounts of calcium. The findings suggest that BI-1 saves cells by interdicting a "death signal" between the ER and the mitochondria and by curbing calcium release. BI-1 seems to fine-tune apoptosis, so cranking up its activity might slow cell suicide without promoting cancer, says co-author Stuart Lipton, also of the Burnham Institute.
"What's intriguing is that BI-1 does appear to affect calcium homeostasis in the ER," says molecular biologist Gordon Shore of McGill University in Montreal, Canada. The question is how, he says. Before it resorts to apoptosis, a damaged cell usually activates a "survival pathway" that works furiously to make repairs, Shore says. We need further research to determine whether BI-1 rescues cells by mobilizing the survival pathway or by blocking apoptosis, he says. Answering that question might reveal how to persuade cells to persevere.
August 18, 2004
Science of Aging Knowledge Environment. ISSN 1539-6150