title: Mutant ubiquitin UBB+1 induces mitochondrial fusion by destabilizing mitochondrial fission-specific proteins and confers resistance to oxidative stress-induced cell death in astrocytic cells.
abstract: Mutant ubiquitin UBB+1 is observed in a variety of aging-related neurodegenerative diseases and acts as a potent inhibitor of the ubiquitin proteasome system (UPS). In the present study, we investigated the relationship between impaired UPS (using ectopic expression of UBB+1) and mitochondrial dynamics in astrocytes, which are the most abundant glial cells in the central nervous system. Immunocytochemistry and fluorescence recovery after photobleaching revealed that ectopic expression of UBB+1 induced mitochondrial elongation. We further demonstrated that overexpression of UBB+1 destabilized mitochondrial fission-specific proteins including Drp1, Fis1, and OPA3, but not the mitochondrial fusion-specific proteins Mfn1, Mfn2, and OPA1. The reduction in mitochondrial fission-specific proteins by UBB+1 was prevented by inhibiting the 26 S proteasome using chemical inhibitors, including MG132, lactacystin and epoxomicin. We then assessed the involvement of proteases that target mitochondrial proteins by using various protease inhibitors. Finally, we confirmed that either overexpression of UBB+1 or inhibiting the proteasome can protect astrocytic cells from H2O2-induced cell death compared with control cells. Our results suggest that UBB+1 destabilizes mitochondrial fission-specific proteins, leading to mitochondrial fusion and the subsequent resistance to oxidative stress. We therefore propose a protective role of UBB+1 overexpression or the proteasome inhibition in astrocytes in degenerative brains.
authors.affiliation: Cell Signaling and BioImaging Laboratory, Department of Bio and Brain Engineering, KAIST, Daejeon, Korea.
authors.forename: Nambin
authors.initials: N
authors.lastname: Yim
authors.affiliation: Cell Signaling and BioImaging Laboratory, Department of Bio and Brain Engineering, KAIST, Daejeon, Korea; KI for the BioCentury, KAIST, Daejeon, Korea.
authors.forename: Seung-Wook
authors.initials: SW
authors.lastname: Ryu
authors.affiliation: Graduate School of Medical Science and Engineering, KAIST, Daejeon, Korea.
authors.forename: Eun Chun
authors.initials: EC
authors.lastname: Han
authors.affiliation: Cell Signaling and BioImaging Laboratory, Department of Bio and Brain Engineering, KAIST, Daejeon, Korea.
authors.forename: Jonghee
authors.initials: J
authors.lastname: Yoon
authors.affiliation: Cell Signaling and BioImaging Laboratory, Department of Bio and Brain Engineering, KAIST, Daejeon, Korea.
authors.forename: Kyungsun
authors.initials: K
authors.lastname: Choi
authors.affiliation: Cell Signaling and BioImaging Laboratory, Department of Bio and Brain Engineering, KAIST, Daejeon, Korea; Graduate School of Medical Science and Engineering, KAIST, Daejeon, Korea; KI for the BioCentury, KAIST, Daejeon, Korea.
authors.forename: Chulhee
authors.initials: C
authors.lastname: Choi
mesh_terms: D001253:Astrocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D006801:Humans; D063154:Mitochondrial Dynamics / Q000187:drug effects; D050505:Mutant Proteins / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000494:pharmacology; D025801:Ubiquitin / Q000378:metabolism*
chemical_list: D050505:Mutant Proteins; D061988:Proteasome Inhibitors; D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex