直近一年間の累計
アクセス数 : ?
ダウンロード数 : ?
ID 118618
著者
Ray, Manobendro Nath Tokushima University
Kiyofuji, Michiko Tokushima University
キーワード
Vitamin E succinate
GRP75
ER-mitochondria contact
Ca2+ transfer
Apoptosis
資料タイプ
学術雑誌論文
抄録
Vitamin E succinate (VES) is an esterified form of natural α-tocopherol, has turned out to be novel anticancer agent. However, its anticancer mechanisms have not been illustrated. Previously, we reported VES mediated Ca2+ release from the endoplasmic reticulum (ER) causes mitochondrial Ca2+ overload, leading to mitochondrial depolarization and apoptosis. Here, we elucidated the mechanism of VES-induced Ca2+ transfer from ER to mitochondria by investigating the role of VES in ER-mitochondria contact formation. Transmission electron microscopic observation confirms VES mediated ER-mitochondria contact while fluorescence microscopic analysis revealed that VES increased mitochondria-associated ER membrane (MAM) formation. Pre-treatment with the inositol 1,4,5-triphosphate receptor (IP3R) antagonist 2-aminoethyl diphenylborinate (2-APB) decreased VES-induced MAM formation, suggesting the involvement of VES-induced Ca2+ efflux from ER in MAM formation. The ER IP3R receptor is known to interact with voltage-dependent anion channels (VDAC) via the chaperone glucose-regulated protein 75 kDa (GRP75) to bring ER and mitochondria nearby. Although we revealed that VES treatment does not affect GRP75 protein level, it increases GRP75 localization in the MAM. In addition, the inhibition of Ca2+ release from ER by 2-APB decreases GRP75 localization in the MAM, suggesting the possibility of Ca2+-induced conformational change of GRP75 that promotes formation of the IP3R-GRP75-VDAC complex and thereby encourages MAM formation. This study identifies the mechanism of VES-induced enhanced Ca2+ transfer from ER to mitochondria, which causes mitochondrial Ca2+ overload leading to apoptosis.
掲載誌名
Biochimica et Biophysica Acta (BBA) - General Subjects
ISSN
03044165
18728006
cat書誌ID
AA00564679
AA11522932
出版者
Elsevier
1867
12
開始ページ
130485
発行日
2023-10-12
備考
論文本文は2024-10-12以降公開予定
権利情報
© 2023. This manuscript version is made available under the CC-BY-NC-ND 4.0 license https://creativecommons.org/licenses/by-nc-nd/4.0/
EDB ID
出版社版DOI
出版社版URL
言語
eng
著者版フラグ
その他
部局
薬学系