Mitochondria comprise two membrane systems, a bordering outer membrane and an invaginated inner membrane containing the oxidative phosphorylation machinery for ATP synthesis. Most mitochondrial membrane proteins are produced as precursors in the cytosolic compartment of the cell and imported into the organelle, whereas only few proteins are synthesized in the mitochondrial matrix. The topologically correct integration of hydrophobic precursor proteins into phospholipid bilayers is a particular challenge for protein translocation systems. Because of this mechanistic complexity, membrane proteins with distinct transmembrane topologies require profoundly different biogenesis pathways. Here we discuss recent findings on the structure and function of the diverse molecular machineries for mitochondrial membrane protein insertion.
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