Mitochondria are vital cellular organelles, which convert chemical energy into ATP in a process termed oxidative phosphorylation. The enzymes mediating oxidative phosphorylation contain many protein subunits. The majority of these subunits is encoded in the nuclear DNA and produced in the cytoplasm, after which they are transported into mitochondria to assemble into the oxidative phosphorylation enzymes. Importantly, a small set of subunits is produced within the organelle. Hence, the production of subunits in the two locations needs to be coordinated to provide subunits in roughly similar quantities for the subsequent assembly. Previous work has indicated that this occurs through feedback loops that operate inside mitochondria to downregulate mitochondrial synthesis of these subunits when they cannot assemble. How these feedback loops operate mechanistically has been unknown. In a study published in Molecular Cell, scientists from the Department of Biochemistry and Biophysics at Stockholm University have now identified how this works for one of the feedback loops.

The feedback loop under investigation couples efficiency to assemble the mitochondrial encoded cytochrome b with translational regulation. The messenger RNA (mRNA), which contains the information for cytochrome b synthesis, is normally used by the mitochondrial ribosome to make new cytochrome b protein. However, under conditions when this cytochrome b cannot assemble, the protein is bound by an assembly helper to stabilize it. Importantly, under these conditions, synthesis of new cytochrome b is blocked through the binding of the mRNA to a region on the ribosome where it cannot be used for protein synthesis. When assembly of cytochrome b liberates the helper protein, it will reactivate translation by releasing the mRNA.

“These results are very surprising and thought-provoking.”, says Martin Ott, the senior author of this study. “We have identified the general concept of translational regulation of cytochrome b synthesis roughly ten years ago, but it took us a long time to figure out how the mechanism operates exactly. Without long-term funding by the Knut and Alice Wallenberg foundation, we would not have been able to pursue such an intricate project. Now we finally can see these elaborate mechanisms working, which have evolved to coordinate gene expression in the nucleus and in the mitochondria. However, many open questions regarding the mechanisms of mitochondrial protein synthesis remain that we would like to answer.” In December, the Knut and Alice Wallenberg foundation has announced that this project will be funded for another five years in the frame of their academy fellows program.


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