Association of Omi/HtrA2 with γ-secretase in mitochondria.
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 γ-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 γ-secretase complexes located to mitochondria. Using a biotinylated γ-secretase inhibitor and confocal microscopy, we could further confirm the association of γ-secretase complexes with mitochondrial Omi/HtrA2. Furthermore, determination of γ-secretase complex topology in isolated mitochondria revealed an association of γ-secretase complexes with the outer membrane of mitochondria with the extreme PS1 C-terminus facing the inter-membrane space. We have also studied the impact of Omi/HtrA2 on γ-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 γ-secretase activity. Thus, our results provide information for understanding the interplay between mitochondrial Omi/HtrA2 and γ-secretase complexes in AD.
Behbahani
Homira
H
Karolinska Institutet and Dainippon Sumitomo Pharma Alzheimer Center (KASPAC), Department of Neurobiology, Care Sciences and Society (NVS), Karolinska Institutet, Huddinge, Sweden. homira.behbahani@ki.se
Pavlov
Pavel F
PF
Wiehager
Birgitta
B
Nishimura
Takeshi
T
Winblad
Bengt
B
Ankarcrona
Maria
M
D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D004591:Electrophoresis, Polyacrylamide Gel; D000074923:High-Temperature Requirement A Serine Peptidase 2; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012697:Serine Endopeptidases / Q000378:metabolism*
D024101:Mitochondrial Proteins; D053829:Amyloid Precursor Protein Secretases; D012697:Serine Endopeptidases; D000074923:High-Temperature Requirement A Serine Peptidase 2; C000615915:Htra2 protein, mouse