MitoMemInsert · Structural determination and dynamics of the mitochondrial import protein (MIM) by cryo-EM and magic-angle-spinning (MAS) nuclear magnetic resonance (NMR)

Structural determination and dynamics of the mitochondrial import protein (MIM) by cryo-EM and magic-angle-spinning (MAS) nuclear magnetic resonance (NMR)

Mitochondria are involved in many cellular processes, including numerous essential metabolic reactions, sensing, ageing and cell death. They are particularly well known as the "powerhouse" of the cell, because they generate the energy, in form of adenosine triphosphate (ATP) which is used as the main "energy currency" of the cell. Mitochondria are believed to stem from a merging event, billions of years ago, of a bacterium (now the mitochondrion) with a predecessor of archaeal cell, which is thought to be the event that allowed for eukaryotic life, and thus all higher forms of life, to emerge. Along evolution, mitochondria have transferred almost the entirety of they genetic material to the nucleus, where it is better protected from damage than in the vicinity of the energy-producing machineries of the mitochondria. Consequently, 99% of the proteins that work in mitochondria are encoded in the DNA in the nucleus, and are made outside the mitochondrion, in the cytoplasm. An important question in this context is therefore how all these proteins are imported into the mitochondrion, i.e., brought from their place of synthesis in the cytosol to their final "work place" in the mitochondrion. This import is particularly tricky for mitochondrial membrane proteins: they are inherently insoluble in water and therefore they need a tightly controlled "shuttle" to avoid them from aggregating in the cytoplasm. Moreover, they need a machinery which inserts them into their final destination in the membrane (outer or inner mitochondrial membrane), and possibly also a channel to cross the outer membrane of the mitochondrion, namely for those membrane proteins that ultimately get inserted into the inner membrane. As the proteins are initially unfolded, namely right after their synthesis, they also need to refold to the correct three-dimensional structure in their final destination. Cells have developed a complex machinery to safely import, refold and insert mitochondrial proteins. This is essential for eukaryotic life, because failure of import of proteins can have catastrophic consequences for the cell; dysfunctional mutations in the import-machinery components is often lethal very early on, and even small deficiencies of import are related to human diseases. Deciphering the function of the machineries involved in mitochondrial import is, therefore, not only of fundamental interest but possibly has implications for understanding human diseases. The goal of this project was/is to characterize a so-called membrane-protein insertase of mitochondria, in terms of its 3D structure, function and interaction with to-be-inserted membrane proteins.

Data: CORDIS, © European Union