Regulation of Mitofusin1 by Mahogunin Ring Finger-1 and the proteasome modulates mitochondrial fusion

• Published in: Biochimica et biophysica acta Vol. 1863; no. 12; pp. 3065 - 3083
• Main Authors: Mukherjee, Rukmini, Chakrabarti, Oishee
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01-12-2016
• Subjects: Animals; beta Karyopherins - genetics; beta Karyopherins - metabolism; Cell Line, Tumor; Fibroblasts - cytology; Fibroblasts - metabolism; Fusion; Gene Expression Regulation; GTP Phosphohydrolases - genetics; GTP Phosphohydrolases - metabolism; HeLa Cells; Humans; Melanocytes - cytology; Melanocytes - metabolism; Mfn1; MGRN1; Mice; Mitochondria; Mitochondria - genetics; Mitochondria - metabolism; Mitochondrial Dynamics - genetics; Mitochondrial Membrane Transport Proteins - genetics; Mitochondrial Membrane Transport Proteins - metabolism; Neurons - cytology; Neurons - metabolism; Proteasome Endopeptidase Complex - metabolism; Protein Multimerization; Proteolysis; Signal Transduction; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism; Ubiquitination; CM-H2DCFDA; DTT; MGRN1; HR; MITOL; RIPA; Drp1; GFP; CCCP; Mitochondria; Ubiquitination; Mfn; Opa1; RING; Mfn1; USP30; ERMES; RFP; OM; Mdm30; Ubp; YFP; BN-PAGE; IM; MUL1; MOM; ER; LUBAC; ROI; Ub; MEF; SOD1; PA; PINK1; NA; PEG; HEPES; Fzo1; ROS; MAM; MARCH; HA; GTPase; NEMO; Fusion
• ISSN: 0167-4889; 0006-3002; 1879-2596
• DOI: 10.1016/j.bbamcr.2016.09.022

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.
•MGRN1 interacts with and constitutively polyubiquitinates Mfn1 via K63 linkages.•Tethering of mitochondria is independent of MGRN1-mediated ubiquitination.•MGRN1-mediated Mfn1 ubiquitination stabilizes Mfn1 oligomers.•Proteasomal processing follows Mfn1 ubiquitination and requires functional p97.•Proteasomal processing is essential for mitochondrial fusion.