title: Regulation of Mitofusin1 by Mahogunin Ring Finger-1 and the proteasome modulates mitochondrial fusion.
abstract: Health and homoeostasis are maintained by a dynamic balance between mitochondrial fission and fusion. Mitochondrial fusion machinery is largely unknown in mammals. Only a few reports have illustrated the role of Fzo1 in mitochondrial fusion known in Saccharomyces cerevisiae. We demonstrate that the ubiquitin ligase Mahogunin Ring Finger-1 (MGRN1) interacts with and constitutively ubiquitinates the mammalian homolog, Mitofusin1 (Mfn1) via K63 linkages. In mice models, loss of Mgrn1 function leads to severe developmental defects and adult-onset spongiform neurodegeneration, similar to prion diseases. The tethering of mitochondria to form the ~180kDa Mfn1 complex is independent of MGRN1-mediated ubiquitination. However, successful mitochondrial fusion requires formation of higher oligomers of Mfn1 which in turn needs GTPase activity, intact heptad repeats of Mfn1 and ubiquitination by MGRN1. Following ubiquitination, proteasomal processing of Mfn1 completes the mitochondrial fusion process. This step requires functional p97 activity. These findings suggest a sequence of events where GTPase activity of Mfn1 and tethering of adjacent mitochondria precedes its MGRN1-mediated ubiquitination and proteasomal degradation culminating in mitochondrial fusion.
authors.affiliation: Biophysics & Structural Genomics Division, Saha Institute of Nuclear Physics, 1/AF Bidhannagar, Kolkata, 700064, India.
authors.forename: Rukmini
authors.initials: R
authors.lastname: Mukherjee
authors.affiliation: Biophysics & Structural Genomics Division, Saha Institute of Nuclear Physics, 1/AF Bidhannagar, Kolkata, 700064, India. Electronic address: oishee.chakrabarti@saha.ac.in.
authors.forename: Oishee
authors.initials: O
authors.lastname: Chakrabarti
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D020558:GTP Phosphohydrolases / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D008544:Melanocytes / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000235:genetics* / Q000378:metabolism; D063154:Mitochondrial Dynamics / Q000235:genetics*; D033681:Mitochondrial Membrane Transport Proteins / Q000235:genetics* / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D055503:Protein Multimerization; D059748:Proteolysis; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism; D054875:Ubiquitination; D028961:beta Karyopherins / Q000235:genetics / Q000378:metabolism
chemical_list: C424166:KPNB1 protein, human; D033681:Mitochondrial Membrane Transport Proteins; D028961:beta Karyopherins; C470690:MGRN1 protein, human; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex; D020558:GTP Phosphohydrolases; C470017:Mfn1 protein, human
keywords: Fusion; MGRN1; Mfn1; Mitochondria; Ubiquitination