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Mitochondrial Biogenesis

Research group
Active research
Project owner
Institute of Biomedicine

Short description

Mitochondrial gene expression contributes a few key subunits to the oxidative phosphorylation system, a key machinery for cellular metabolism. The main goal of this project is to unravel how protein synthesis by mitochondrial ribosomes is connected to downstream processes including protein biogenesis and quality control. Martin Ott's group employs a combination of protein biochemistry, genetics and high-resolution single particle cryo-electron microscopy to reveal basic molecular mechanisms. Because the respiratory chain is crucial for cellular energy metabolism, defects of mitochondrial gene expression result in severe human diseases. Hence, the information emerging from these studies will be relevant for basic as well as for medical sciences.

The food we eat contains a variety of molecules in the form of sugar or fat that provide the energy that sustanin the body's various processes. However, the various constituents of food cannot be used directly as energy but must first be broken down via a series of chemical reactions to finally form the cell's energy currency ATP. The final steps in this important energy conversion take place in the cell's power plant, the mitochondria, where the protein complexes of the respiratory chain carry out the formation of ATP. The respiratory chain is absolutely necessary for the survival of our cells and a variety of processes must work together for the complexes to become assembled. The different subunits must be present at the right time, in the right place and in the right proportions. An additional complexity is that the proteins in the respiratory chain have two different origins. Some are produced inside the mitochondria and others outside the mitochondria. Assembling these proteins into a complete respiratory chain requires advanced coordination between protein production inside the mitochondria and the import of the proteins produced outside the mitochondria. If this coordination does not work as it should, it can have devastating consequences in the form of serious illnesses.

How then are the import and synthesis of proteins linked to how they are joined to the different protein complexes of the respiratory chain? This is exactly what the group wants to clarify. Through past research, there is now a relatively good knowledge of how the protein complexes in the respiratory chain are put together, but many major questions remain. Therefore, the research group is investing in detail the molecular mechanisms of mitochondrial protein synthesis. The strategy is to combine classical biochemistry, modern structural biology and powerful genetics in yeast and human cells to achieve a deep understanding of this unexplored process. The main focus is to understand three essential aspects of protein synthesis: (i) In what order and by what factors does protein synthesis in mitochondria initiated and how is it regulated. (ii) How is the expression of the large number of proteins included in the respiratory chain coordinated and how are they assembled? (iii) How accurate is mitochondrial protein synthesis and how does it affect organellar proteostasis?

Energy conversion mediated by the mitochondrial respiratory chain is necessary for cellular metabolism and functions. Knowledge of this vital process is therefore central to both basic science and the understanding of various disease states. New knowledge can pave the way for the development of completely new strategies for treating various diseases (eg neurodegenerative disease and cancer) and aging, where impaired mitochondrial function plays an important role.