Mutant ubiquitin UBB+1 induces mitochondrial fusion by destabilizing mitochondrial fission-specific proteins in astrocytic cells = 사람성상세포에서 돌연변이 유비퀴틴 UBB+1에 의한 미토콘드리아 분열 단백질 불안정에 관한 연구

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Mutant ubiquitinB+1 (UBB+1) and abnormal changes of mitochondrial dynamics are commonly observed in a broad array of aging-related neurodegenerative diseases such as Alzheimer’s disease and Pick’s disease. Previous studies demonstrated that UBB+1 acts as a potent inhibitor of ubiquitin proteasome pathway and impairs the function of mitochondria in the neuronal cells. In this study, I investigated the relationship between UBB+1 and mitochondrial dynamics in human astrocytic cells. Immunocytochemistry and fluorescence recovery after photobleaching (FRAP) analysis showed that ectopic expression of UBB+1 affects mitochondrial dynamics to fusion. Overexpression of UBB+1 destabilized mitochondrial fission-specific proteins including Drp1, Fis1, and OPA3, but not mitochondrial fusion-specific proteins, Mfn1, Mfn2, and OPA1. The destabilization of mitochondrial fission-specific proteins by UBB+1 is recapitulated by 26S proteasome inhibition using proteasome inhibitors MG132 and Lactacystin. Among various protease inhibitors, Indinavir affected the stability of mitochondrial fission-specific proteins in UBB+1 stable expressing cells. Using lactate dehydrogenase assay and TMRE staining, I observed UBB+1 stable expressing cells have less sensitive to hydrogen peroxide induced oxidative stress compared to the control cells by the regulation of mitochondrial dynamics more fusion state. Collecting, my results demonstrate that UBB+1 destabilizes mitochondrial fission-specific proteins through the activation of proteases in 26S proteasome dependent manner and induces a mitochondrial fusion state resulting in increased resistance against oxidative stress, re-lighting the role of UBB+1 in neurodegenerative diseases.
Choi, Chul-Heeresearcher최철희
한국과학기술원 : 바이오및뇌공학과,
Issue Date
566286/325007  / 020123571

학위논문(석사) - 한국과학기술원 : 바이오및뇌공학과, 2013.8, [ vi, 40 p. ]


Mutant ubiquitin; 산화 스트레스; 세포 사멸; 신경퇴화질환; 미토콘드리아 동역학; 돌연변이 유비퀴틴; UBB+1; Mitochondrial Dynamics; Neurodegenerative diseases; Cell death; Oxidative stress

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