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Research

Biogenesis of Mitochondria

 

 

We are studying protein sorting processes into and within mitochondria. These are complex reactions, as every protein has to be routed to its specific destination within the organelle.

 

We employ biochemical, genetic, cell biological and immunological techniques with Saccharomyces cerevisiae and Neurospora crassa as model systems to explore the function of mitochondrial translocases which, in a concerted fashion, mediate import and sorting of proteins into the mitochondrial subcompartments.

 

 

Biogenesis of Inner Membrane Proteins

One main focus of our group is the biogenesis of proteins of the mitochondrial inner membrane which belongs to the protein-richest membranes of the eukaryotic cell. It accommodates a large number of different integral membrane proteins which, typically assembled in multiprotein complexes, perform a variety of functions like the transport of molecules or generation of ATP. We analyze how these proteins are inserted into the inner membrane, and identify and characterize components that mediate this process. There are several different insertion pathways into the inner membrane. Proteins can either be inserted from the intermembrane space side by the TIM translocases. Alternatively, proteins can be embedded from the matrix side in a process that resembles protein insertion reactions in bacteria in several respects. The Oxa1 complex plays an important role in this insertion process and our goal is to characterize the precise function and significance of this potential translocase. Employing different biochemical approaches we investigate the molecular mechanisms by which the TIM and OXA complexes interact with their substrates and mediate their insertion into or translocation across the lipid bilayer. In addition, we try to identify the signals which qualify a substrate protein for its specific insertion pathway and warrant its final topology in the membrane.

We recently could show that the Oxa1 complex contains a C-terminal domain that binds to mitochondrial ribosomes. This interaction is important for membrane insertion of mitochondrial translation products. This suggests that a cotranslational insertion mode of mitochondrially encoded proteins is achieved by a physical coupling of the ribosome and the Oxa1 translocase.

Import of proteins into the intermembrane space

A second project in our group focuses on the processes by which proteins are translocated into the intermembrane space. Although the overall number of proteins in this compartment is probably rather small, intermembrane proteins attracted a lot of attention recently since they play crucial roles in important cellular processes like energy generation or apoptosis. Little is known about the processes that allow their translocation into the intermembrane space.

Many proteins of the intermembrane space do not contain mitochondrial presequences. Instead they contain conserved patterns of cyteine residues which are essential for targeting. We recently identified a system in the intermembrane space that introduces disulfide bonds into newly imported proteins. This system consists of the sulfhydryl oxidase Erv1 and of Mia40 which presumably functions as an import receptor. Both components use the oxidation of cysteine residues to drive the import process. Most likely the oxidation locks the proteins in a tightly folded conformation and thereby prevents the backtranslocation of the polypeptides into the cytosol. On the basis of our observations we proposed a 'folding ratchet mechanism' according to which the free diffusion of a protein across the outer membrane is rectified by its irreversible folding in the intermembrane space. The movie below shows an animation of our model of the Erv1-Mia40-mediated import process.