Regulation of mitochondrial fusion by ubiquitylation of mitofusin

• Applicant: Dr. Mafalda Escobar-Henriques
• Subject Area: Biochemistry
• Term: from 2014 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 261074682

Mitochondrial fusion recently joined a group of fundamental processes, such as transcription or cellular trafficking, which are controlled by ubiquitylation. Interestingly, mitochondrial dynamics, arising from constantly occurring fusion and fission events, was only discovered in the late nineties. Such plasticity, required to maintain mitochondrial function, is essential for embryonic development, neuronal survival or apoptosis. The main components in the fusion of mitochondrial outer membranes are mitofusins. Called Fzo1 in yeast and Mfn1 and Mfn2 in mammals, they are highly conserved proteins, whose dysfunction has been associated with human disease. Mutations in Mfn2 cause Charcot-Marie-Tooth type 2A neuropathy and ubiquitylation of mitofusins by the E3 ligase Parkin contributes to the elimination of damaged mitochondria by mitophagy, and may play a protective role against Parkinson disease. Two different pathways control the ubiquitylation and turnover of the yeast mitofusin Fzo1. Ubiquitylation of Fzo1 under stress conditions by an unknown ligase leads to mitochondrial fragmentation. On the other hand, constitutive ubiquitylation of Fzo1 depends on the SCFMdm30 and is necessary for mitochondrial fusion. Mitofusins are Dymamin-related GTPase proteins, whose function requires self-association. We found that Mdm30 only ubiquitylates Fzo1 following Fzo1 oligomerization and GTP hydrolysis. This led us to propose a first model for outer membrane fusion, where Fzo1 ubiquitylation drives completion of fusion.Here, we want to understand how ubiquitylation regulates mitochondrial fusion. We will employ genetic and biochemical approaches to identify new components and elucidate this mechanism at the molecular level. In addition, we will investigate the functional significance of the unusual and conserved ubiquitylation pattern of mitofusins beyond mitochondrial fusion. We expect to open new perspectives into the general mechanisms guiding membrane remodelling by ubiquitylation that will also be of relevance for our understanding of the role of mitofusins for neuronal survival.

• DFG Programme: Research Grants
• International Connection: United Kingdom, USA
• Participating Persons: Professor Dr. Gunnar Dittmar; Professor Dr. Jürgen Dohmen; Dr. Suzanne Hoppins, Ph.D.; Professor Dr. David Komander