Research focus

Mitochondria are the powerhouse of eukaryotic cells and produce the bulk of cellular ATP through oxidative phophorylation. Moreover, mitochondria fulfil additional important cellular tasks such as the generation of FeS-clusters, they are involved in amino acid and lipid metabolism, and the regulation of programmed cell death.

Most of the approximately 1000 mitochondrial proteins are imported from the cytosol into mitochondria post-translationally. However, a small number of hydrophobic proteins are synthesized within mitochondria.

We are interested in understanding the molecular mechanisms by which proteins are transported across the mitochondrial membranes and to find out how multi-protein complexes in the inner membrane (TIM complexes; translocation machineries of the inner membrane) mediate this task. In another aspect of our work we addresses the question as to how newly imported proteins assemble into multi-protein complexes in the inner membrane. In case of the respiratory chain complexes the assembly process is especially demanding since central subunits of the complexes are made within mitochondria. Dedicated chaperone-like factors are required to assist and regulate the assembly process. The analysis of the principles of the biogenesis process and the activities of the assembly factors is of central importance for our understanding of the molecular basis of human mitochondrial disorders. In our work we combine biochemical and genetic techniques on the model organism Saccharomyces cerevisae with experiments in human cell lines. Research topics that we currently address are:

Transport and membrane insertion of mitochondrial proteins.

Assembly of inner mitochondrial membrane complexes and how this process is affected in mitochondrial disorders.

Biogenesis of mitochondrially-encoded proteins.

Current topics

  1. Protein dynamics of protein translocases during precursor transport
  2. Mechanisms of translational regulation in mitochondria – a molecular basis for human disorders
  3. Recent publications of our work are listed on the Webpage
  4. For further questions, please do not hesitate to contact Peter Rehling

ERC-MITRAC

Mitochondrial translational regulation coupled to respiratory chain assembly and protein import

Mitochondrial respiratory chain complexes assemble from nuclear- and mitochondria-encoded subunits in the inner membrane. To protect cells from accumulating unassembled subunits in the membrane, ROS generation, or damage of mitochondrial integrity, regulatory mechanisms to balance and control the fidelity of the assembly process have evolved, encorporating a retention system enabling the preservation of a select few founding complexes for on-demand assembly. In yeast mitochondria, a feedback mechanism has been identified for the cytochrome oxidase in which assembly-intermediates specifically inactivate translation of the core subunit Cox1. It is controversially debated if similar translation regulating mechanisms exist in human mitochondria. However, our recent findings show that in human mitochondria assembly intermediates of respiratory chain complexes affect translation, nevertheless the underlying sensing and signalling mechanisms as well as the protein components appear to be more complex than in yeast. We aim to understand how this regulatory cycle is established; how does a distinct assembly intermediate of cytochrome oxidase signal the translation system, and how the influx of imported subunits contributes to this process. These goals are conceptually deeply rooted in a comprehensive understanding of the membrane protein complex assembly process and the factors that promote its progression. These objectives are of key importance for understanding the molecular pathology of mitochondrial encephalomyopathies that are frequently due to respiratory chain assembly and quality control malfunction. The aim of our analyses is to provide insight as to how translation can be coupled to the assembly of a membrane protein complex comprised of subunits of dual genetic origin and to decipher mitochondrial translational regulation coupling to the influx of imported nuclear encoded subunits.