The cell-autonomous role of Afg3l2 in mitochondrial dynamics and neurodegeneration

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Fine control of mitochondrial functions is essential in neurons, as underlined by the pathogenic role of mitochondrial dysfunction in neurodegeneration. Recently, m-AAA mitochondrial proteases in the inner mitochondrial membrane have been associated to human neurodegenerative diseases. m- AAA proteases degrade misfolded and non assembled polypeptides, thus performing quality control surveillance in the organelle. Moreover, they regulate the activity of specific substrates by mediating essential processing steps. One of these is the mitochondrial fusion molecule OPA1, linking the mitochondrial proteolytic system and the associated human diseases to defects in mitochondrial fusion. This proposal aims at investigating the cell-autonomous role of the m-AAA protease in mediating neurodegeneration and regulating mitochondrial dynamics, by employing a conditional mouse model of Afg3l2, the main subunit of m-AAA proteases expressed in the brain. By deleting Afg3l2 specifically in postnatal neurons, astrocytes, or myelin forming cells, and by analyzing the neuropathological phenotype of the various models, as well as the effect on mitochondrial morphology, fusion ability, distribution, transport, and turnover, we expect to shed light both on pathogenic mechanisms leading to neurodegeneration and on basic aspects of integrated mitochondrial functions in the brain.