P05 - Molecular characterization of MICOS-dependent inner mitochondrial membrane morphology biogenesis

One of the morphology defining elements of the inner mitochondrial membrane are cristae junctions (CJs). These membrane segments display high degrees of membrane curvature and connect inner boundary membranes with cristae membranes. The multi-subunit MICOS complex is required to maintain and probably form cristae junctions. MICOS consists of proteins with the ability to bend membranes and to form extensive protein-protein interaction networks. While some progress has been made in attributing specific functions to single MICOS subunits a detailed understanding of how the various complex proteins act in a concerted manner but also with other proteins and with lipids is largely missing. We will use complementary biochemical, biophysical and cell biological approaches to unravel the role of MICOS as a membrane shaping and organizing hub at a molecular level. As a first aim, we will reconstitute the minimal MICOS network required for membrane shaping and membrane contact site formation. Various model membrane systems together with purified proteins will be employed to first reconstitute MICOS dependent membrane bridging. In a second step these structures will be used to co-reconstitute membrane bridging and MICOS dependent membrane remodeling within the same system. Results from this part of the project will unravel the minimal unit that establishes membrane contact sites and cristae organization, the two main function of MICOS. For the second aim we will take a step closer towards the physiological situation in mitochondria.

We will characterize the two recently identified MICOS subcomplexes on a molecular level. Subunit specific and, importantly, lipid specific effects on membrane bridging and membrane bending will be analyzed. Finally, we aim to characterize the interaction between MICOS and Opa1. Opa1 is a protein important for normal cristae morphology and involved in the regulation of CJ opening, which is critical for cytochrome c release during the intrinsic apoptotic pathway. Molecular details of this protein-protein interaction will be characterized. The reciprocal effects of Opa1 and MICOS on membrane morphology will be analyzed to start to understand how MICOS functions are integrated into processes carried out by other inner membrane proteins.