Researchers have produced an in-depth snapshot of how the cellular machines that produce proteins in mitochondria are assembled. This creates insight into essential cellular mechanisms involved in many diseases, including neurodegenerative disorders and heart disease.
Billions of years ago in the ancient primordial swamp, a cell tried to devour a bacterial cell, as it had done many times before, but this time things changed. Instead of being consumed, the bacterial cell ended up becoming part of the larger cell, and when it divided, so did the bacterial cell.
Fast forward to the present, and this random encounter between two cells billions of years ago still affects life today. Over time, the larger cell developed into eukaryotic cells, which comprise all animals and plants, and the bacterial cell has become the mitochondria present in all plant and animal cells, including human cells.
The cooperation between these two types of cells has also developed over time, and mitochondria are essential for much of life on Earth today. Mitochondria generate most of the chemical energy that powers biochemical reactions in cells. They even have their own DNA and synthesise their own proteins.
Much more has been learned about how proteins are synthesised since researchers have now discovered how the mitochondrial ribosome, which makes the mitochondria’s proteins, is assembled.
“We have known for some time how the mitochondrial ribosome looks, but the process by which it is formed has remained more mysterious. We have now taken a structural snapshot of this process, and this improves understanding of how mitochondria maintain their function. If they do not function properly, this can lead to the development of neurodegenerative disorders and heart disease,” explains a researcher behind the study, Eva Kummer, Associate Professor, Novo Nordisk Foundation Center for Protein Research at the University of Copenhagen, Denmark.
The research has been published in Nature Communications.
Thirteen proteins have their own assembly mechanism
The mitochondrial ribosome differs greatly from that present in the cytosol (cell fluid) of the cells. It also differs considerably between organisms, while the ribosome in the cytosol looks rather similar in all organisms .
Mitochondrial ribosomes are special because they only produce 13 proteins. Nevertheless, the mitochondria maintain a distinct mechanism for translating DNA into these proteins, and there can only be one explanation for this.
“The cells expend tremendous effort to maintain this extra mechanism that makes only 13 proteins. The ribosomes in the cytosol make thousands of proteins. This shows how important these 13 proteins are. All are parts of the respiratory signalling pathway that ultimately enables the mitochondria to produce ATP, the cellular energy molecule,” says Eva Kummer.
Eighty molecules are assembled to form one complete ribosome
The researchers isolated mitochondrial ribosomes from human cells to discover how the ribosomes are formed. Each cell has mitochondrial ribosomes in various stages of development.
Some are fully developed, and others are being assembled by using the approximately 80 components used to create mitochondrial ribosomes.
Using single-particle cryoelectron microscopy, the researchers captured images of the stages of ribosomal development.
Then they processed the data to organise the images and determine the some of the steps along the process that leads from 80 biomolecules to a complete ribosome.
“Research in this field has focused mostly on the final stages of development, in which the incomplete ribosome is stable and easier to study, but there has been very little knowledge about the initial and intermediate stages. We also investigated the intermediate stages, specifically how the larger of two subunits of the mitochondrial ribosome is synthesised,” explains Eva Kummer.
Basis of life on Earth
Eva Kummer and colleagues determined what happens in three maturation steps towards creating the larger of the two ribosomal subunits.
More specifically, the researchers describe the creation of the three steps that synthesise the ribosome’s catalytic site – where the protein’s amino acids are assembled one by one in a long chain.
They also describe how the GTPases GTPBP7 and GTPBP10 work together to fold the RNA that becomes part of the catalytic site in the ribosome.
This step is also interesting, because mitochondria apparently use two GTPases, whereas bacteria – from which mitochondria originate – only use one.
“Researchers thought that GTPBP7 ensures the chemical modification of the RNA when it becomes part of the ribosome. We have discovered in our structures that it rather protects the RNA as a scaffold that enables the other protein, GTPBP10, to enter and place the RNA in this subunit of the ribosome. What is interesting from a basic science viewpoint is that the RNA is not just any piece of RNA but the RNA in the catalytic part of the ribosome. It is one of the most important pieces of RNA in the ribosome and thus essential for producing energy in the mitochondria and the functioning of cells and all multicellular life on Earth,” concludes Eva Kummer.
“Structural insights into the role of GTPBP10 in the RNA maturation of the mitoribosome” has been published in Nature Communications. The research was supported through a Hallas-Møller Emerging Investigator grant from the Novo Nordisk Foundation.
