Nerve Cells' Power Plants Caught In A Traffic Jam

Rather than moving to the ends of the cells, or synapses, wherecell-to-cell communication takes place, mitochondria in mutant fruitflies just piled up in the center of the cell. Even so, the mutantcells could still transmit signals, although not as well.

The findings are surprising because scientists had thought anydisruption in normal mitochondrial behavior would be lethal in theembryo stage. Instead, the mutant fruit fly larvae survive for fivedays, although they don't live to adulthood.

"Everyone believed that mitochondria are essential at synapses -- andthis is wrong," said Konrad E. Zinsmaier, the University of Arizonaassociate professor of neuroscience who led the research team. "Themutation allows us to study what mitochondria are really good for." Thefinding provides scientists with additional insight into how nervecells work and provides a basis for understanding how such dysfunctionscause neurodegenerative diseases.

The researchers will publish their findings in the August 4 issue ofthe journal Neuron. A complete list of authors and their affiliationscan be found at the end of this release.

Little is known about what causes mitochondria to becomedysfunctional and how they contribute to neurological disorders. Tolearn more about what could go wrong with the energy units, Zinsmaierand his colleagues induced a mutation in the fruit fly mitochondrialprotein, dMiro. dMiro stands for Drosophila mitochondrial Rho-likeGTPase.

Molecular motors shuttle mitochondria within cells along cellularhighways called microtubules. Normally, the mitochondria travel thelength of the neuron until they reach the synapse. The mutation in thedMiro protein disabled the motor, disrupting the normal pattern ofmitochondrial distribution.

The nerves' synapses are where one nerve cell connects andcommunicates with other cells. For example, muscle cells contract whenthey receive the proper signals from nerve cells. Abnormalmitochondrial distribution within a neuron alters its ability to signalproperly to adjoining muscle or nerve cells.

Instead of cruising smoothly along the microtubules, the mitochondriain mutant cells become caught in a traffic jam at the entrance ramp,located in the cell's center.

Even though the synapses of the mutants are entirely devoid ofmitochondria, the neuronal function remained intact at low levels ofstimulation. But at high levels of stimulation, the mutated nerve cellsfailed.

Zinsmaier is now questioning the purpose of the mitochondria at thesynapse. "How important are mitochondria?" he said. "We were surprisedat how long the system could survive without them." Zinsmaier explainedthat there may be a compensatory mechanism in place that is able todeal with minor mitochondrial dysfunction within the nerve.

Besides providing energy, mitochondria carry out other tasks importantfor cell survival. One important mitochondrial task is taking up excesscalcium. Calcium is the main ingredient for proper neuron function. Toomuch calcium can lead to cell death. Zinsmaier hypothesizes that therecould be a specialized communication system established within neuronsinvolving another cell component that cooperates with mitochondria toproperly store calcium.

While he has begun to piece together several theories, Zinsmaierexplained that it remains unclear exactly how the compensation occurs."The real surprise is that there are mechanisms in place that canmanage the system somehow," he said. "We didn't know about them."

The findings made by Zinsmaier and his colleagues havesignificant implications for neurobiologists, who may now begin lookingmore closely at defects in mitochondrial transport. Alterations in thisprocess may help explain how and why human neurological diseases, suchas muscular dystrophy and spastic paraplegia, develop.

The paper is titled "The GTPase dMiro is Required for Axonal Transportof Mitochondria to Drosophila Synapses." The authors, listed in orderfrom first to last, are Xiufang Guo of The University of Arizona andthe University of Pennsylvania School of Medicine; Greg T. Macleod ofThe University of Arizona and the University of Toronto; AndreaWellington, Fangle Hu, Sarvari Panchumarthi and Miriam Schoenfield ofThe University of Arizona; Leo Marin, Milton P. Charlton and Harold L.Atwood of the University of Toronto; and Konrad E. Zinsmaier of TheUniversity of Arizona.

The research was funded by the National Science Foundation and the Natural Sciences and Engineering Research Council of Canada.