Pitt Neuroscientists Uncover Mechanism For Neuron Death, Counter Long-Held,,Assumptions About Th...( ese enzymes arecritical to the functio...)

"We discovered that neurons can tolerate 20 times more calcium than what was formerly believed to be lethal, as long as this calcium doesn't get inside mitochondria," said Amy Stout, first author on the paper and a post-doctoral student investigator in Dr. Reynold's lab.

Calcium influx into mitochondria appears to trip a death switch for neurons, whereas changes in calcium-sensitive enzymes within the cytoplasm are like dimmer switches that change the health of a neuron by degrees, according to Dr. Reynolds.

In their studies, the investigators cultured neurons from the forebrains of rats and exposed them to varying concentrations of calcium. In some cases, they also exposed the cells to chemicals that block the uptake of calcium by mitochondria. Cells that received high levels of calcium but no mitochondrial blockers died. Cells that were exposed to high calcium concentrations and mitochondrial calcium blockers lived.

Calcium ultimately may ruin mitochondria through a number of mechanisms, according to Dr. Reynolds. Normally, mitochondria can absorb excess calcium from cells. But constantly cycling calcium out of the cytoplasm may sap mitochondria of energy they normally produce to charge cells. Calcium influx also can spur the formation of free radicals that damage mitochondrial DNA or inevitably rip holes in the mitochondrial membrane.

Together with Teresa Hasting, Ph.D., assistant professor of neurology at Pitt, Dr. Reynolds recently received a more-than $1 million federal grant to study mitochondrial responses in neuronal injury.

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Contact: Lauren Ward
wardle@msx.upmc.edu
(412) 624-2607
University of Pittsburgh Medical Center
4-Sep-1998