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 by the nuclear DNA and produced in the cytoplasm. Afterwards, they are transported into mitochondria to be assembled into the oxidative phosphorylation enzymes. Importantly, a small set of subunits is produced within the organelle by a dedicated gene expression system. In the course of evolution, many aspects of gene expression in mitochondria have been modified. How the multiple processes mediated by various proteins are mechanistically coupled and spatially organized has been unknown. In a study published in Molecular Cell, scientists from the Department of Biochemistry and Biophysics at Stockholm University have now revealed a molecular roadmap detailing this connectivity.

Gene expression operates universally by a sequence of steps known as the central dogma of molecular biology. Specifically, genes encoded in DNA are first transcribed into messenger RNAs, which are then translated into proteins by a large molecular machine termed ribosome. During all these steps, auxiliary proteins maintain the flow through the central dogma by direct interactions. While the individual steps have been studied in isolation, this newly published study takes a holistic approach and reveals the precise interactions as they occur at important sites of the gene expression machinery. To this end, the team led by Martin Ott utilized a technique termed BioID, by which the proteins present in close proximity of a certain protein can be identified with high confidence. Repeating these analyses for multiple other bait proteins and coupling it with proteomics and network biology, allowed to construct a roadmap that revealed important mechanistic insights into gene expression. Furthermore, the data obtained represent a valuable resource for future studies and is accessible by everybody via an open-source online application. An immediate outcome of the work is that gene expression and the subsequent assembly of the newly synthesized proteins are directly coupled, similar to the production pipeline for a car engine that is then directly connected to the assembly site, where the car is put together.

“These results are very surprising and thought-provoking” says Abeer Singh, a lead author of this study, “We have identified the general organization of mitochondrial gene expression and how it connects to respiratory chain assembly. Many of the findings indicate novel pathways and it will be exciting to figure out how they operate exactly. Another crucial aspect of this study was the collaboration with the group of Axel Imhof in Munich. Their expertise in mass-spectrometry was essential and we had many exciting discussions.” This study is supported by the Knut and Alice Wallenberg foundation and their academy fellows program, the Swedish research council and Carl Tryggers foundation.


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