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.
Dennerlein, S., Oeljeklaus, S., Jans, D., Hellwig, C., Bareth, B., Jakobs, S., Deckers, M., Warscheid, B., Rehling, P. (2015), MITRAC7 Acts as a COX1-Specific Chaperone and Reveals a Checkpoint during Cytochrome c Oxidase Assembly. Cell Rep. [Epub ahead of print]
Pacheu-Grau, P., Bareth, B., Dudek, J., Juris, L., Vögtle, F.-N., Wissel, M., Leary, S., Dennerlein, S., Rehling, P., Deckers, M. (2015), Cooperation between COA6 and SCO2 in COX2 maturation during cytochrome c oxidase assembly links two mitochondrial cardiomyopathies. Cell Metabolism 21, 823-833
Dennerlein, S., Rehling, P. (2015), Human mitochondrial COX1 assembly into cytochrome c oxidase at a glance. J. Cell Sci. 128, 833-837