Mitochondria are not single isolated organelles but constitute a real network comparable to the Endoplasmic Reticulum or the Golgi apparatus. In wild type conditions, this network adopts a tubular morphology that is conditioned by active and constant processes of fission and fusion of mitochondrial membranes.Unlike other organelles, fusion of mitochondrial membranes is not catalyzed by SNAREs but involves two sets of large GTPases, the mitofusins and OPA/Mgm1, involved in fusion of outer and inner membranes, respectively. Consequently, these GTPases not only participate in transmission of mitochondrial DNA and therefore oxidative phosphorylation but also play a major role in apoptosis. In addition, impairment of mitochondrial fusion is directly linked to several neurodegenerative syndromes such as Parkinson and Charcot-Marie Tooth diseases as well as Dominant Optic Atrophy. The importance of elucidating the mechanism underlying mitochondrial fusion therefore becomes evident.We have previously shown that Fzo1, the yeast mitofusin, is subject to exquisite regulation by the Ubiquitin-Proteasome System. Based on this, we will aim at dissecting the involvement of the ubiquitin-proteasome system in movement, tethering and fusion of outer and inner membranes. To reach this goal, multidisciplinary in vivo and in vitro approaches will be employed, including genetics, biochemistry and cell biology imaging techniques.Besides elucidating molecular mechanisms underlying mitochondrial fusion, the present project is likely to generate concepts that may apply to all membrane fusion events within eukaryotic cells. Contributions to understanding of neuropathies directly caused by defects of mitochondrial dynamics are also to be expected.