Newly Identified Role For 'Power Plants' In Human Cells Could Lead To Targeted T

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Newly Identified Role For 'Power Plants' In Human Cells Could Lead To

Targeted Therapies

http://medicalnewscenter.com/out/out.cgi?

http://www.sciencedaily.com/releases/2008/06/080624110949.htm

Scientists have determined that human cells are able to shift

important gene products into their own mitochondria, considered the

power plants of cells. The finding could eventually lead to therapies

for dozens of diseases.

The gene products, known as tRNAs, assemble amino acids for the

production of proteins within mitochondria. If the mitochondrial tRNA

genes are defective or missing, and proteins are not manufactured,

the mitochondria are unable to generate adequate energy.

Defective tRNAs are believed to be the cause of about 60 percent of

conditions traced to malfunctions in the mitochondria. The range of

related conditions includes diabetes, hearing loss and a number of

neurological disorders, depending on which kinds of cells are

affected.

Mitochondria are encased in their own membrane, making them a

structure that is complicated to study. Previous research has

suggested that only in lower organisms, such as protozoans, yeast and

plants, can tRNAs be imported to the mitochondria from the cell

cytoplasm, the fluid-based area that contains most components of a

cell.

But in this new research, scientists determined that tRNAs can be

imported from cytoplasm to mitochondria in rat liver cells and human

cells as well.

" This was totally unexpected, to find an innate, built-in mechanism

that we humans have, " said Alfonzo, senior author of the study

and an assistant professor of microbiology at Ohio State University.

The finding broadens the study of therapeutic options involving

attempts to introduce healthy tRNAs to the defective mitochondria of

ill patients, Alfonzo said.

" If you have a mutation in a tRNA that you suspect is involved in

disease, you theoretically should be able to bring a healthy tRNA

from the cytoplasm into the mitochondria and correct the

malfunction, " he said.

The research appears online this week in the Proceedings of the

National Academy of Sciences.

Alfonzo noted that the current study was able to determine that the

import of tRNAs occurs, but it leaves open the question of how it

happens.

He and colleagues conducted experiments first in rat liver cells to

test whether tRNA import occurs in mammals at all. When the import

was observed in rat mitochondria, they extended the study to human

cells.

The finding that tRNA import occurs in humans can set in motion an

entirely new line of research into therapeutic options for patients

with diseases caused by mitochondrial defects. There appears to be no

way to introduce healthy tRNAs directly into mitochondria because

their membranes have proven impenetrable to such outside

interference, Alfonzo explained.

So scientists know they would have to rely on the import process that

starts in the cytoplasm to transfer healthy tRNAs to damaged

mitochondria and improve energy production.

Until now, researchers didn't know the human mitochondria had that

import ability, so scientists were going to try using protozoan or

yeast cells to manipulate the import process in human cells.

" What we are saying is you don't need to bring up new machinery from

a different organism because human cells already come equipped with

their own way to import tRNAs. There is no need to cross species, "

Alfonzo said. " What we need to know now is what proteins are involved

in the import mechanism so we can exploit the process for therapy. "

One compound already identified as essential for the process is

Adenosine-5-triphosphate, or ATP, a compound associated with energy

transport in cells. Alfonzo and colleagues demonstrated ATP's role in

the process using cells from a patient with a specific type of

epilepsy called MERRF. This disease is characterized by a

mitochondrial tRNA mutation leading to a drastic reduction in the

mitochondria's ability to generate ATP, which in turn hinders the

import of tRNAs into the mitochondria of people with this disease.

When ATP was introduced to the mitochondria of these diseased cells,

the import process of tRNAs from the cytoplasm to the mitochondria

was restored.

" These were cells from an actual patient, so this also makes the

argument that we don't need a surrogate system from other organisms

to set the import process in motion, " Alfonzo said.

Alfonzo conducted this work with Anne Rubio of Ohio State's

Department of Microbiology; Rinehart, Bethany Krett and Dieter

Söll of Yale University's departments of molecular biophysics and

biochemistry and chemistry; and Stéphane Duvezin-Caubet and s

Reichert of the Institute for Physiological Chemistry at Ludwig-

Maximilians-University in Munich.

This research was supported by grants from the Deutsche

Forschungsgemeinschaft (German Research Foundation), the National

Institute of General Medical Sciences and the National Science

Foundation.