| Co-Investigator(Kenkyū-buntansha) |
OGAWA Satoshi Kanazawa University, Graduate School of Medical Science, Professor, 医学系研究科, 教授 (90283746)
KITAO Yasuko Kanazawa University, Graduate School of Medical Science, Assistant Professor, 医学系研究科, 助手 (00019613)
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| Budget Amount *help |
¥3,000,000 (Direct Cost: ¥3,000,000)
Fiscal Year 2004: ¥600,000 (Direct Cost: ¥600,000)
Fiscal Year 2003: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 2002: ¥1,200,000 (Direct Cost: ¥1,200,000)
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| Research Abstract |
When SH-SY5Y cells, human-derived neuroblastoma cell lines, were treated with endoplasmic reticulum (ER) stress inducers such as tunicamycin or thapcigargin, unbalanced expressions of mitochondrial proteins were observed in cytochmme C oxidase (COX) subunits as reported in HeLa cells (Hori et al., J.Cell Biol.2002). Similar phenomena were obtained, together with enhanced unfolded protein response (UPR) in the ER, when treating SH-SY5Y cells with MPP+, a mitochondrial toxin which induces Parkinson disease-like neurodegeneration in vitro and in vivo. These results suggest the existence of stress transmission in both ways between the mitochondria and the ER (a spiral of the intracellular stress.). Lon protease, a mitochondrial ATP-dependent protease, and GRP75/mtHSP70, a molecular chaperon in the mitochondria, are both induced in response to ER stress to maintain the mitocondrial function under those conditions in HeLa cells (Hori et al., J.Cell Biol.2002). However, in SH-SY5Y cells, both mitochondrial proteins were not induced in response to ER stress or MPP+ treatment, when compared with the expressions of regular UPR-related genes such as GRP78 or CHOP. These observations suggest that the transmission of stress response from the ER to mitochondria were weakened in neuronal cells.
Characterization of Lon KO mouse was performed. Lon (-/-) embryos were died around E8.5-E9.5, and severe growth retardation, especially in mesoderm) was observed in E7.5. Morphological studies revealed that enhanced production of reactive oxygen species (ROS) and cell death were observed in Lon (-/-) embryos at E7.5. Mitochondrial DNA amounts were reduced in Lon (-/-) embryos compared with wt ones at E7.5. These results suggest that Lon protease play an important role in the mesoderm development by maintaining mtDNA stability or replication.
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