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Neuroscientists Uncover Mechanism For Neuron Death, Counter Long-Held Assumptions About This Process

Date:
September 8, 1998
Source:
University Of Pittsburgh Medical Center
Summary:
An influx of calcium specifically into mitochondria appears to trigger the death of neurons exposed to glutamate, a neurotransmitter that proves toxic when it's overproduced in traumatic brain injury and stroke. The finding derails a long-held assumption that high concentrations of calcium within a cell's cytoplasm - and not in the mitochondria -- causes cells to die.

PITTSBURGH, Sept. 4 -- An influx of calcium specifically into mitochondria appears to trigger the death of neurons exposed to glutamate, a neurotransmitter that proves toxic when it's overproduced in traumatic brain injury and stroke. This research finding, presented by University of Pittsburgh investigators in the September issue of Nature Neuroscience, derails a long-held assumption that high concentrations of calcium within a cell's cytoplasm - and not in the mitochondria -- causes cells to die.

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"In our research, we found that neurons can accumulate high amounts of calcium inside the cytoplasm without breaking down. It's only when large amounts of calcium flow into mitochondria that neurons die," said Ian Reynolds, Ph.D., associate professor of pharmacology at the University of Pittsburgh School Medicine.

"This information clearly shows that we should consider designing drugs to target mitochondria to prevent or intervene in glutamate-induced neuronal damage," said Dr. Reynolds. Specific calcium channels on the surface of mitochrondria may prove one important target for drug design, he added.

As with all living cells, a neuron consists of a cell membrane enclosing fluid cytoplasm. Within the cytoplasm are intracellular organelles, including mitochondria. Mitochondria are kidney-shaped organelles that have their own DNA and which produce energy for cells to function.

Glutamate works by binding to receptors on the surface of a neuron. This binding activates an influx of calcium that triggers the neuron to release additional glutamate, which stimulates other neurons, resulting in neurotransmission. Sometimes, however, injured or diseased nerves release too much glutamate. Excess glutamate over-stimulates neurons. The resultant neurotoxicity causes cell death.

Traditionally, neuroscientists have thought that too much calcium would perturb calcium-sensitive enzymes within the cytoplasm. These enzymes are critical to the function of a neuron. Several research teams have suggested that the disturbance of these enzymes, rather than any problems with mitochondria, mediate cell death.

"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.


Story Source:

The above story is based on materials provided by University Of Pittsburgh Medical Center. Note: Materials may be edited for content and length.


Cite This Page:

University Of Pittsburgh Medical Center. "Neuroscientists Uncover Mechanism For Neuron Death, Counter Long-Held Assumptions About This Process." ScienceDaily. ScienceDaily, 8 September 1998. <www.sciencedaily.com/releases/1998/09/980908074335.htm>.
University Of Pittsburgh Medical Center. (1998, September 8). Neuroscientists Uncover Mechanism For Neuron Death, Counter Long-Held Assumptions About This Process. ScienceDaily. Retrieved November 20, 2014 from www.sciencedaily.com/releases/1998/09/980908074335.htm
University Of Pittsburgh Medical Center. "Neuroscientists Uncover Mechanism For Neuron Death, Counter Long-Held Assumptions About This Process." ScienceDaily. www.sciencedaily.com/releases/1998/09/980908074335.htm (accessed November 20, 2014).

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