2003 Fiscal Year Final Research Report Summary
The mechanism of protection of apoptosis by the mitochondrial PHGPx
| Project/Area Number |
14572063
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Biological pharmacy
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| Research Institution | Kitasato University |
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Principal Investigator |
NAKAGAWA Yasuhito Kitasato University, School of Pharmaceutical Sciences, Professor, 薬学部, 教授 (00119603)
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| Co-Investigator(Kenkyū-buntansha) |
KOUMURA Tomoko Kitasato University, School of Pharmaceutical, Research Associate, 薬学部, 助手 (30337985)
今井 浩孝 北里大学, 薬学部, 助教授 (50255361)
HIROTAKA Imai Kitasato University, School of Pharmaceutical, Associate Professor (30337985)
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| Project Period (FY) |
2002 – 2003
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| Keywords | cardiolipin / mitochondria / glutathione peroxidase / cytochrome c / apoptosis |
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| Research Abstract |
In this project, we try to find out the mechanism of the protection of apoptosis mitochondrial type of phospholipid hydroperoxide glutathione peroxidase (PHGPx). Apoptosis caused by 2deoxyglucose was completely suppressed by the overexpression of mitochondrial PHGPx. The release of cytochrome c (cyt.c) provide the irreversible signal of apoptosis. Overexpression of mitochondrial PHGPx inhibit the release of cyt.c from mitochondria. There are two steps for the liberation of cyt. C from mitochondria. First step is the dissociation of cyt.c from inner membrane of mitochondria and second step is the passage of free cyt. C through the permeability transition pore (PT pore) which regulates the opening by adenine nucleotide translocator (ANT).
Cyt.c preferentially binds to the monolayer of cardiolipin which is the specific phospholipid in mitochondria. Binding of cyt.c to CL monolayer significantly decreased by the autooxidation of CL. Cyt.c released from liposome containing CL by the peroxidation with radical initiator, these results suggest that cytc could release from inner membrane of mitochondoria.
ANT activity was significantly decreased by the induction of apoptosis. Inactivation of ANT was well correspond to the liberation of cyt. C from mitochondria. ANT activity of mitochondria markedly inhibited by the fusion of CLOOH with isolated mitochondria suggesting that CLOOH could inhibit ANT activity. ANT activity of reconstituted proteoliposome was suppressed by the addition of CLOOH in proteoliposome.
These results suggest that peroxidation of CL as a mitochondrial specific phospholipid might be a key step to initiate the apoptosis.
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[Publications] Imai, H., Hirao, F., Sakamoto, T., Sekine, K., Mizukura, Y., Saito, M., Kitamoto, T, Hayasaka, M., Hanaoka, K., Nakagawa, Y.: "Early embryonic lethality caused by targeted disruption of the mouse PNGPx gene."Biochemical and Biophysical Research Communications. 305. 278-286 (2003)
Description
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