Spying on Misbehaving Mitochondria

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WASHINGTON, D.C.--Just as military brass covet surveillance of enemy operations, biologists like to peer inside defective cells to understand what's going on. Now, a new light microscopy technique is offering an unparalleled view of the inner workings of living cells. The videos suggest tantalizing links between the shape and function of defective cell parts, offering insight into how genetic defects contribute to disease.

In devastating diseases such as Leigh's syndrome or fatal infantile lactic acidosis, a genetic defect sabotages the cellular power plants called mitochondria. This breakdown disrupts metabolism and deforms nerves and muscle. Until now, scientists trying to investigate these defective mitochondria have been limited to techniques that stain, damage, and even kill cells, which they worry interferes with their ability to watch a malfunctioning cell in action.

To circumvent these problems, physicist Tim Richardson and colleagues from the Hospital for Sick Children in Toronto, Canada, went back to square one. They redesigned light microscopy to allow a view of cells fresh from the human body and left unstained, they reported 11 December at the annual meeting of the American Society for Cell Biology here. But because their technique has not yet been patented, the group declined to give details on their methods. Richardson would say only that the new approach differs from confocal and difference interference contrast, two microscopy techniques that are laser- and light-based, respectively. However, the new technique is sill based on light.

To test the new approach, Richardson's team observed mitochondria in healthy skin cells and in skin cells taken from people with mitochondrial diseases. Magnified 12,500 times, the healthy mitochondria clearly resembled the long filaments seen with other imaging techniques. But, surprisingly, the organelles scooted around the cell far faster than expected, suggesting that mitochondria are more dynamic than previously thought. The diseased mitochondria, in contrast, looked like little lollipops and barely moved. "We have no understanding [of the relationship] between mitochondrial form and function," says team member and biologist Nhu-An Pham, who hopes her group's videos will change that.

"The pictures are intriguing," says mitochondrial researcher Robert Balaban of the National Heart, Lung, and Blood Institute in Bethesda, Maryland. But, he adds, this new view of mitochondria could be tainted by the approach used to gather images. "They need controls to show the behavior isn't due to their observation technique," he says.

Posted in Biology