Biological membranes are complex structures built up of a multiplicity of membrane lipids and proteins controlling essential cellular processes. This is exemplified by mitochondria, dynamic double-membrane bound organelles, with essential roles in diverse metabolic and cellular signalling pathways. The mitochondrial inner membrane is considered to be the protein richest cellular membrane, whose functional impairment is associated with aging, myopathies and diverse neurological disorders in human. Recent evidence from our group revealed essential roles of large, ring-like prohibitin complexes in the inner membrane for embryonic development in mice, cell proliferation, resistance against apoptosis, and the maintenance of mitochondrial cristae. Prohibitins comprise a conserved and ubiquitously expressed protein family and are suggested to serve as protein scaffolds in the inner membrane. Defining the network of genetic interactions in yeast, we could establish that prohibitin function depends on the supply of the non-bilayer phospholipids cardiolipin and phosphatidyl ethanolamine and on intramitochondrial lipid trafficking. These findings indicate that mitochondrial function and ultrastructure requires a defined spatial organization of the inner membrane, which is maintained by a defined lipid composition and prohibitins serving as protein scaffolds. Here, we propose a comprehensive analysis of the function of prohibitins and of novel components involved in mitochondrial lipid trafficking and phospholipid biosynthetic pathways. These studies will include genetic as well as biochemical and proteomic approaches and employ both yeast and murine models to integrate the molecular understanding of functionally conserved processes into the physiological context. As components of this system have been linked to cardiomyopathies and diverse neurological disorders, our studies are likely to provide new insight into pathomechanisms of human disease.
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