Modulation of mitochondrial function and morphology by interaction of Omi/HtrA2 with the mitochondrial fusion factor OPA1

被引：56

作者：

Kieper, Nicole ^{[1
,2
]}

Holmstroem, Kira M. ^{[1
,2
]}

Ciceri, Dalila ^{[1
,2
]}

Fiesel, Fabienne C. ^{[1
,2
]}

Wolburg, Hartwig ^{[3
]}

Ziviani, Elena ^{[4
]}

Whitworth, Alexander J. ^{[4
]}

Martins, L. Miguel ^{[5
]}

Kahle, Philipp J. ^{[1
,2
]}

Krueger, Rejko ^{[1
,2
]}

机构：

[1] Univ Clin Tubingen, Ctr Neurol, D-72076 Tubingen, Germany

[2] Hertie Inst Clin Brain Res, D-72076 Tubingen, Germany

[3] Univ Tubingen, Inst Pathol, D-72076 Tubingen, Germany

[4] Univ Sheffield, Med Res Council, Ctr Dev & Biomed Genet, Sheffield S10 2TN, S Yorkshire, England

[5] MRC Toxicol Unit, Cell Death Regulat Lab, Leicester LE1 9HN, Leics, England

来源：

EXPERIMENTAL CELL RESEARCH | 2010年 / 316卷 / 07期

基金：

英国惠康基金;

关键词：

Omi; HtrA2; Mitochondria; Fusion; OPA1; Parkinson's disease; SERINE-PROTEASE HTRA2/OMI; LOSS-OF-FUNCTION; STRIATAL NEURONS; APOPTOSIS; DYSFUNCTION; MUTATIONS; PATHWAY; DISEASE; STRESS; PINK1;

D O I：

10.1016/j.yexcr.2010.01.005

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Loss of Omi/HtrA2 function leads to nerve cell loss in mouse models and has been linked to neurodegeneration in Parkinson's and Huntington's disease. Omi/HtrA2 is a serine protease released as a pro-apoptotic factor from the mitochondrial intermembrane space into the cytosol. Under physiological conditions, Omi/HtrA2 is thought to be involved in protection against cellular stress, but the cytological and molecular mechanisms are not clear. Omi/HtrA2 deficiency caused an accumulation of reactive oxygen species and reduced mitochondrial membrane potential. In Omi/HtrA2 knockout mouse embryonic fibroblasts, as well as in Omi/HtrA2 silenced human HeLa cells and Drosophila S2R+ cells, we found elongated mitochondria by live cell imaging. Electron microscopy confirmed the mitochondrial morphology alterations and showed abnormal cristae structure. Examining the levels of proteins involved in mitochondrial fusion, we found a selective up-regulation of more soluble OPA1 protein. Complementation of knockout cells with wild-type Omi/HtrA2 but not with the protease mutant [S306A]Omi/HtrA2 reversed the mitochondrial elongation phenotype and OPA1 alterations. Finally, co-immunoprecipitation showed direct interaction of Omi/HtrA2 with endogenous OPA1. Thus, we show for the first time a direct effect of loss of Omi/HtrA2 on mitochondrial morphology and demonstrate a novel role of this mitochondrial serine protease in the modulation of OPA1. Our results underscore a critical role of impaired mitochondrial dynamics in neurodegenerative disorders. (C) 2010 Elsevier Inc. All rights reserved.

引用

页码：1213 / 1224

页数：12

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