Association of Omi/HtrA2 with γ-secretase in mitochondria

被引：37

作者：

Behbahani, Homira ^{[1
,2
]}

Pavlov, Pavel F. ^{[2
]}

Wiehager, Birgitta ^{[2
]}

Nishimura, Takeshi ^{[3
]}

Winblad, Bengt ^{[2
]}

Ankarcrona, Maria ^{[2
]}

机构：

[1] Karolinska Inst, NVS, KASPAC, SE-14157 Huddinge, Sweden

[2] Karolinska Inst, Dainippon Sumitomo Pharma Alzheimer Ctr KASPAC, Dept Neurobiol Care Sci & Soc NVS, SE-14157 Huddinge, Sweden

[3] Dainippon Sumitomo Pharma Co Ltd, Pharmacol Res Labs, Osaka, Japan

来源：

NEUROCHEMISTRY INTERNATIONAL | 2010年 / 57卷 / 06期

关键词：

Omi/HtrA2; Presenilin; gamma-Secretase; Mitochondria; AICD; AMYLOID PRECURSOR PROTEIN; SERINE-PROTEASE; HTRA FAMILY; PDZ DOMAINS; TOPOLOGY; PRESENILIN-1; HTRA2/OMI; BRAIN; INTERACTS; ELEGANS;

D O I：

10.1016/j.neuint.2010.08.004

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Omi/HtrA2, a mitochondrial serine protease with chaperone activity, is involved in varied intracellular processes. Dysfunctional Omi/HtrA2 has thus been implicated in various neurodegenerative disorders. Previously, we have shown that gamma-secretase complexes are present and active in mitochondria. Here, we demonstrate that peptide corresponding to C-terminus of presenilin-1, as previously reported to activate Omi/HtrA2, interacts with Omi/HtrA2 in isolated mitochondria. Moreover, we show that Omi/HtrA2 interacts with presenilin in active gamma-secretase complexes located to mitochondria. Using a biotinylated gamma-secretase inhibitor and confocal microscopy, we could further confirm the association of gamma-secretase complexes with mitochondrial Omi/HtrA2. Furthermore, determination of gamma-secretase complex topology in isolated mitochondria revealed an association of gamma-secretase complexes with the outer membrane of mitochondria with the extreme PSI C-terminus facing the inter-membrane space. We have also studied the impact of Omi/HtrA2 on gamma-secretase activity, measuring APP intracellular domain (AICD) production. We found reduced AICD production in mitochondria isolated from Omi/HtrA2 knockout mouse embryonic fibroblasts, indicating a significant role of Omi/HtrA2 on gamma-secretase activity. Thus, our results provide information for understanding the interplay between mitochondria! Omi/HtrA2 and gamma-secretase complexes in AD. (c) 2010 Elsevier Ltd. All rights reserved.

引用

页码：668 / 675

页数：8

共 43 条

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