Mystery of the mitochondria

Postdoctoral scholar Fabiana Perocchi remembers her Ph.D. advisor once telling her that if you want to go from a million candidates to a few thousand, you need to find something that does not agree with the pattern. When she joined Vamsi Mootha’s lab at the Broad Institute and Massachusetts General Hospital three years ago to investigate mitochondria – the powerhouses of cells – Fabiana learned about an intriguing phenomenon: mitochondria found in the cells of humans and most other organisms can soak up large amounts of calcium ions, but no one knows precisely how or why. Researchers had long suspected that there was a channel, a sort of molecular passageway on the surface of mitochondria, that allowed these charged particles to enter and kickstart a number of metabolic processes, but no one had been able to pinpoint the protein that formed this channel known as the uniporter.

Since her background was in yeast genetics, Fabiana was curious to find out if mitochondria in this single-celled model organism shared this calcium-absorbing capability. They did not.

“I was surprised so I read more and more to see if it was a lack of knowledge or if it really was absent,” Fabiana recalls. Fabiana soon realized that she had found something that did not agree with the pattern.

Using yeast as an exception, the team was able to narrow in on their first clue: a protein called MICU1, which appeared to help mitochondria sense calcium. But they needed to find MICU1’s partner proteins in the cell to reveal the identity of the uniporter. Around the time that Fabiana and her colleagues submitted a paper about the findings, her colleague Josh Baughman, a graduate student in the Mootha lab, offered up his help in the form of a computational algorithm he had been working on.

Up until that time, Josh had been working on separate projects in the lab, building a computational system that could help researchers look for patterns of genes commonly expressed together. Josh was also developing a library of RNA interference molecules to shut off each of the mitochondrial genes.

When Josh ran MICU1 through his program, the results were better than the team had expected. The gene that was expressed most similarly to MICU1 was one that had happened to come up in Josh’s previous studies.

“We had this incredible head start because of this random connection between the two projects,” says Josh. “Fabiana and I decided the best way to do this was to work together.”

Josh put aside his graduate work to devote his time to finding the elusive calcium channel. “It was a very risky, all in bet for me,” he admits. “I was putting aside a whole chapter of my dissertation…if I’d lost the gamble, it would have meant another year in graduate school.”

Luckily for Josh, the many hours he and Fabiana and their colleagues spent on the project paid off. Using a multi-pronged approach, the team centered in on one protein, which it dubbed MCU. In a paper published this week, the researchers present evidence indicating that MCU is a component of the uniporter channel that researchers have been hunting for the last 50 years.

How important is this discovery? It may be too soon to say according to Fabiana and Josh. Scientists have long known that calcium is a major signal that may have hundreds of different functions, telling the cell whether to live or die, to release neurotransmitters or hormones, and much more.

“People have been studying that for a long time and know the importance of calcium as a signal,” says Josh, “but what our work is going to allow them to do is figure out how important mitochondria are in modulating that signal, which just hasn’t been possible until now.”

Fabiana was certainly not the first researcher to notice that yeast mitochondria did not suck up calcium – it is a fact that has been known for four decades. But Fabiana and her colleagues were the first to connect this to experimental methods of narrowing in on the proteins involved in calcium uptake.

“There are so many things published that people have forgotten,” says Fabiana who dove into the old literature for clues. “The whole strategy for how to find this came from integrating different datasets. Knowing what was absent turned out to be very important.”

You can read more about the team’s most recent findings in a Broad news story here or get the full story about their efforts to chart the secrets of these cellular engines in the Project Spotlight story “Mitochondrial Mapmakers.”