EurekAlert: Preventing Mitochondria From Turning Ugly May Postpone Parkinson?s ...

[Murray Charters <mcharters@xxxxxxxxxxxxxx>]

EurekAlert: Preventing Mitochondria From Turning Ugly May Postpone Parkinson?s 
...
Public release date: 23-Sep-2003

Contact: Neal Singer
nsinger@xxxxxxxxxx
505-845-7078
DOE/Sandia National Laboratories

Sandia nanolaser may help extend life-spans by rapidly analyzing possible 
neuroprotectant drugs

Preventing mitochondria from turning ugly may postpone Alzheimer?s, 
Huntington?s, Parkinson?s diseases

ALBUQUERQUE, NM. - Anyone visiting a nursing home has seen the horror of humans 
surviving beyond their brains' ability
to make sense of their surroundings.

That loss of discrimination is caused by neurons killed by malfunctions in 
mitochondria - the submicron-sized power
packs found in every animal cell.

These malfunctions are the most immediate cause of afflictions like 
Parkinson's, Huntington's, and Alzheimer's
diseases.

Malfunctioning mitochondria have also been linked to battlefield aftereffects 
caused by radiation or by nerve agents
like sarin.

But because mitochondria are so small, averaging a few hundred nanometers, 
scientists have been unable to study them in
vitro with the necessary precision to determine the best possible 
neuroprotectants.

Now a unique laser operating in the nanometer range at the Department of 
Energy's Sandia National Laboratories has
demonstrated the first-ever technique for studying the reactions of such 
ultrasmall biological organelles in their
functioning state. The laser, using samples obtained from the University of New 
Mexico School of Medicine, has shown it
can obtain clear signals from individual mitochondria in vitro.

Waterproofing mitochondria

"'Waterproofing' the mitochondria with specific protectant drugs would increase 
the survival chances of the brain,"
says Marcus Keep, a neurosurgeon professor at the University of New Mexico 
School of Medicine.

"Our goal is make the brain less susceptible to diseases like Lou Gehrig's," 
says Sandia researcher Paul Gourley, a
physicist who grew up in a family of doctors.

Work to date has shown the biolaser (which recently won first place in the 
DOE's annual Basic Energy Sciences'
competition for using light to quantify characteristics of anthrax spores) is 
able to measure mitochondrial size
through unexpected bursts of light given up by each mitochondrion. The laser, 
using the same means, can also measure
the swelling effect caused by the addition of calcium ions ( the reaction 
thought to be the agent of death for both
mitochondria and their host cells. The researchers expect to introduce 
neuroprotectant drugs into experiments this
month, and be able to test hundreds of possible protective substances daily 
instead of two or three formerly possible.

"If we can use this light probe to understand how mitochondria in nerve cells 
respond to various stimuli, we may be
able to understand how all cells make life or death decisions - a step on the 
road, perhaps, to longer lives," says
Gourley.

To do that, he says, scientists must understand how a cell self-destructs, 
which means understanding how mitochondria
send out signals that kill cells as well as energize them.

The universal energy provider

Mitochondria have long been known as the mechanism that produces ATP, the 
universal energy driver for animal life. ATP
powers each cell similarly to the way that gas powers each automobile. But 
scientists have found that the tiny power
plants have another function. When cells are signaled to die - acceptably, as 
when biomaterial is shed from a uterus
during its periodic menstrual cycle, or unacceptably, as the result of certain 
neurological diseases - an excess of
calcium ions and free radicals that result from certain chemical reactions in 
the body open a large pore in the inner
membrane in that cell's mitochondria. The pore enables release of a protein 
called cytochrome C that kills the cell.
Meanwhile, the mitochondrion itself swells and explodes. One way to stop this 
suicidal process would be to find a
chemical that would shield the mitochondria from these intruders.

Unexpected bursts of light

The observation technique developed at Sandia to test for such effects came 
about almost by accident. In the innovative
lab arrangement already developed by Gourley's group, a micropump sends fluids 
containing suspect material through a
submicron-sized lasing cavity. The cavity is formed between a light-emitting 
semiconductor and a reflective mirror.

The group expected to push fluid containing mitochondria through the device and 
to see very weak signals emanating from
the tiny organelles. Had this been true, signal-averaging techniques would have 
been necessary to generate a
generalized, necessarily less crisp estimate of responses.

"We were pleasantly surprised but puzzled to see very large signals from each 
mitochondrion," Gourley said. "A
statistical average was unnecessary."

The researchers realized that each mitochondrion acted as a lens for light 
passing through it because the organelle had
a higher index of refraction (1.42) than water (1.33). Light refracted into the 
mitochondria in effect emerged
amplified. It was exactly analogous to a lens concentrating light passing 
through it.

"When a critical concentration of emitted photons is reached," says Gourley, 
"stimulated emission of additional photons
occurs in the semiconductor."

These photons, as well as those reflected from the mirror, retrace their paths 
back through the mitochondria. "Wildly
wayward photons are lost," Gourley says. "Only the photons that pass back 
through the tiny mitochondrion will arrive
back at the semiconductor with the proper phase and location where the photon 
amplification (gain) can recur."

This discovery suggested the laser cavity be set up sensitively - like a gun on 
a hair-trigger - by carefully setting
the power of an external pump laser that beams energy into the cavity. When a 
mitochondria cell is present, the light
in the cavity reaches critical concentration to trigger the avalanche of 
photons necessary for laser action.

Thus the tiny organelle becomes the center of a lasing process that yields 
light signals as bright as that emitted by
an entire cell several orders of magnitude larger, offering possibilities for 
analysis that light scattering - the
current method of choice for rapid mitochondrial analysis - lacks.

Because the light has to squeeze through such a tiny object, a process Gourley 
calls "nano-squeezing," the lasing
spectra are dramatically altered, which makes cell identification and detection 
easier.

UNM's Keep, who is also chief executive officer of the Albuquerque-based 
Swedish-American company Maas BiolAB, has
contributed the neuroprotective agent Cyclosporin A, for which his company 
holds a patent. According to Keep,
Cyclosporin A does "waterproof" the mitochondria, but not well enough. The idea 
here is to use the Sandia biolaser to
establish a benchmark for performance against which to measure other, 
potentially even more effective drugs.

"Cyclosporin protects mitochondria better than anything else known, but it is 
not a perfect drug," says Keep. "It has
side effects, like immunosuppression. Unrelated drugs may have a similar 
protective effect on mitochondria. Gourley's
device will lead to a rapid screening device for hundreds of cyclosporin 
derivatives or even of chemical compounds
never tested before."

While testing with conventional methods would take many people and many batches 
of mitochondria, says Keep, the
nanolaser requires only tiny amounts of mitochondria and drug to test.

"With one tube on the left flowing in a number of mitochondria per second, and 
microliters of different drugs in
different packets flowing in to join them on the right, we could rapidly run 
through hundreds of different compounds.
Each mitochondrion scanned through the analyzer would show if there were a 
change in its lasing characteristics. That
would determine the effectiveness of chemical compounds and identify new and 
even better neuroprotectants."

Currently, he says, only a few materials can be tested each day.

Mitochondria with and without neuroprotectant would have calcium ions added to 
the mix to see the effect of each
potential drug.

The work is funded by DOE's Basic Energy Sciences program, DOE's Office of 
Biological and Environmental Research and
Sandia's Laboratory Directed Research and Development funds.

In addition, Keep has applied for a grant from the US Congress to develop 
treatments based on Cyclosporin A to help
Gulf War victims who develop the neuron disease amyotrophic lateral sclerosis 
(ALS). ALS or Lou Gehrig's disease is a
neurodegenerative disorder affecting both Gulf War veterans and civilians that 
kills motor neurons causing paralysis
and death in three years

###

Story and image available at 


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Managed and Operated by Sandia Corporation
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ALBUQUERQUE, NM 87185-0167
PHONE: 505,844-8066, FAX: 505-844-6367

SOURCE: EurekAlert, DC


Reference:

Sandia Laboratories Nanolaser May Help Extend Life-Spans by Rapidly Analyzing 
Possible Neuroprotectant Drugs Preventing
Mitochondria From Turning Ugly May Postpone Alzheimer's, Huntington's, 
Parkinson's Diseases.
SOURCE: ASCRIBE NEWS via COMTEX / Macro*World Investor


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