Mitochondria are parts of cells that provide the body with energy (among other things), but despite their obvious importance, we are far from knowing everything about them—especially how certain molecules manage to get inside the mitochrondria. Scientists from Monash University have discovered a new technique that allows them to see how any channel protein works, and this could revolutionize medicine as we know it.
Mitochondria have a somewhat complicated structure, including two membranes that surround them and prohibit most kinds of molecules from entering. These membranes are bridged by proteins that help specific molecules get inside the mitochondrion—complexes known as TIM (found on the inside membrane) and TOM (found on the outer membrane).
TOM and TIM control the content and amount of what is allowed through the membrane. Scientists didn’t fully grasp how they worked because of their complex function. Normally, a technology like x-ray crystallography would allow scientists to see the exact shape of the molecule, which in turn would allow them to figure out how it functions. But the mitochondrial membrane proteins have resisted all attempts to be mapped.
Without this information, scientists haven’t been able to figure out which molecules TOM or TIM let in, and under what circumstances—but thanks to the Monash team, one of the complexes, known as TOM40, is no longer a mystery.
Peering into the cell
As reported in Science, the team modified the TOM40 complexes within yeast, injecting a new kind of amino acid into their structure. These amino acids, known as probes, show a somewhat unique interaction with UV light. When a burst of UV is flashed onto the TOM40 complex, these probes reflect the light onto nearby structures—which electron microscopes capture. By moving the amino acids and capturing countless images, the scientists were finally able to assemble a picture of the protein structure—like the world’s hardest 3D jigsaw puzzle made of microscopic pieces.
“How large molecules like proteins get in and out of membranes has long been a mystery,” said lead researcher Professor Trevor Lithgow. “We have shown that this technology can be applied to solve the atomic scale details for all sorts of fundamental pathways going on in cells, opening the way to direct applications for medical research.”
If scientists know how a protein complex like TOM selectively permits over 1000 different kinds of proteins to enter a mitochondrion, they might be able to create drugs that can enter the mitochondrion as needed to help with various diseases. Further, the technique can be used all over the cell, not just in mitochondria—in other key but not fully understood parts.
Someday, we may even be able to directly regulate metabolic disorders, diabetes, processes like DNA damage and repair, or cancer.
“This new technology has revealed what has been a major unknown in biology, and other cellular mysteries are now ripe for the picking,” said Lithgow.
For those in the know
In case you have a background in cellular biology, here’s a general view of how TOM40 works. As the substrate (preproteins) for the complex approaches, an N-terminal segment of the TOM40 channel passes from the cytosol through the channel. Once it reaches the intermembrane space, it recruits chaperones located there. These chaperones guide the transfer of preproteins from the cytosol through the channel and into the intermembrane space.
TOM40 itself contains three β-barrel channels sandwiched between a central α-helical TOM22 receptor cluster and external regulatory TOM proteins. The coupling of chaperones, β-barrel channels, and α-helical receptors is what allows TOM to selectively transport around 1000 different proteins.
—–
Image credit: Thinkstock
Comments