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Mitochondria Don't Just 'Kiss and Run'

06/11/2014
Kayt Sukel

New research on mitochondrial fusion shows that mitochondria are much more than just a cell’s power generators. Read more...


Open any basic biology textbook and you’ll find a similar description of mitochondria, the small ovoid organelles found in all eukaryotic cells. They are known as the “powerhouses” or “power plants” of the cell, generating the adenosine triphosphate (ATP), or chemical energy currency, a cell needs to keep it powered up and working. When György Hajnóczky, Director of the MitoCare Center for Mitochondrial Imaging Research and Diagnostics at Thomas Jefferson University, first started working with mitochondria as a medical student, this role was considered their main function.

György Hajnóczky

“But when you sit at the microscope and watch the mitochondria, you see that they are always moving. It’s like dancing or a piece of art,” said Hajnóczky. “They come together, they seem to fuse with one another, they move apart. But they are always moving up and down and around. And it makes you wonder what they are doing and what it is doing for the cell.”

And with advances in microscopic imaging technologies, it became clear that mitochondrial fusion is a process vital to cell health, extending the mitochondria’s role to overall cell quality control.

“We already knew that mitochondria are critical to energy production. Think about a muscle or a brain cell. They are continuously consuming large amounts of energy. That energy is primarily produced by the mitochondria,” said Hajnóczky. “And so the mitochondria are working all the time. And when you work all the time, things break down. There will be defects, and those defects need to be fixed.”

A biological pit-stop

To deal with those defects and maintain overall cell health, two mitochondria come together and merge both their inner and outer membranes. This fusion allows the two to mix their soluble contents, providing damaged organelles with fresh DNA, proteins, and enzymes before the two mitochondria separate and go on their merry ways. “What’s astonishing is that this whole process can be completed in about two seconds. That’s why we often call it the ‘kiss and run,’” said Hajnóczky. “It’s like a pit stop in Formula One racing. The cars race around the circle and at some point, the tires or some component gets broken and needs to be replaced. So they make a quick stop, have one or two things replaced, and they get back on the road. We think the ‘kiss and run’ is something like this. And, like the car, it keeps the mitochondria running.”

But fusion sometimes requires a bit more than “kiss and run,” so mitochondria also undergo what Hajnóczky calls “complete” fusion. “Think again about the car race. After a Formula One race, you may have to rebuild the whole car. It has bigger maintenance issues. It’s the same with mitochondria,” he said. For rebuilding, two mitochondria will merge with each other and spend enough time together not only to mix their soluble components but also their membranes. This basically rejuvenates the whole mitochondria, improving overall cell function.

Drinking and driving

The highly ordered mitochondrial structure of skeletal muscle (left), and the unexpected mitochondrial networks uncovered in the study (right). The green fluorescence was photoactivated in a 5umx5um square area, and the appearance of the green signal outside the photoactivation area reveals complex networks with matrix continuity. Credit: G Hajnóczky

That rejuvenation is important not only to the cell’s health, but also to the overall health of the organism. For example, the diseases Autosomal Dominant Optic Atrophy and Charcot-Marie-Tooth disease, which both involve muscle weakness, arise in part from mutations of genes involved in regulating mitochondrial fusion. Yet, mitochondrial fusion was not studied in muscle cells since most researchers believed fusion simply couldn’t occur in the tight fibers of muscular tissue.

Hajnóczky and Veronica Eisner, a post-doctoral fellow in his laboratory, genetically engineered the cells of rat skeletal muscle so that the mitochondria expressed red fluorescent protein and a photoactivatable green fluorescent protein. After laser treatment to turn on green fluorescence in a small region, the two researchers followed the red and green fluorescence in the tightly packed cell and showed that mitochondria moved around the cell. The appearance of green fluorescence outside the photoactivated area showed that the organelles mixed contents too, directly challenging the predominant notion that mitochondria could not interact in muscle cells.

The team then went on to look at genes involved with mitochondrial fusion, and learned that one in particular, mitofusion 1 (Mfn1), was responsible for causing muscle weakness not only in mitochondrial diseases but also in environmental diseases like alcoholism.

“People knew about alcoholic myopathy and alcoholic cardio myopathy, dangerous consequences of long-term drinking. But there was no known mechanism for it,” said Hajnóczky. “When we looked at the skeletal muscle of rats that had been drinking alcohol for six months, we found that the fusion activity was wiped out, and Mfn1 was specifically decreased in the alcoholic condition.”

This finding, Eisner said, may provide new therapeutic drug targets for the treatment of muscle weakness symptoms in mitochondrial disease and long-term alcoholism as well as new insights into other diseases that influence muscle tissue.

Hajnóczky hopes that better understanding the key components involved in both “kiss and run” and “complete” fusion will lead to discoveries important for a range of human diseases. The key, he said, is to use a variety of different techniques on living tissues.

“There are things we simply cannot learn from cell cultures,” he said. “But by monitoring mitochondrial fusion in real tissue, we are going to learn a lot more that will inform clinical development. The intelligence of mitochondria has been very much underappreciated. But we are learning that real tissues are much more dependent on mitochondrial fusion, and mitochondrial dynamics as a whole, than we ever knew before. Our very lives depend on the cooperation of mitochondria with the cell.”

Reference

Eisner V, Lenaers G, Hajnóczky G. Mitochondrial fusion is frequent in skeletal muscle and supports excitation-contraction coupling. J Cell Biol. 2014 Apr 28;205(2):179-95.