A Small Molecule Inhibitor of Redox-Regulated Protein Translocation into Mitochondria

被引：72

作者：

Dabir, Deepa V. ^{[1
]}

Hasson, Samuel A. ^{[1
]}

Setoguchi, Kiyoko ^{[2
]}

Johnson, Meghan E. ^{[1
]}

Wongkongkathep, Piriya ^{[1
]}

Douglas, Colin J. ^{[1
]}

Zimmerman, Johannes ^{[1
]}

Damoiseaux, Robert ^{[3
]}

Teitell, Michael A. ^{[2
,4
,5
,6
]}

Koehler, Carla M. ^{[1
,4
,5
,6
]}

机构：

[1] Univ Calif Los Angeles, Dept Chem & Biochem, Los Angeles, CA 90095 USA

[2] Univ Calif Los Angeles, Dept Pathol & Lab Med, Los Angeles, CA 90095 USA

[3] Univ Calif Los Angeles, Los Angeles, CA 90095 USA

[4] Univ Calif Los Angeles, Inst Mol Biol, Los Angeles, CA 90095 USA

[5] Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90095 USA

[6] Univ Calif Los Angeles, Broad Stem Cell Res Ctr, Los Angeles, CA 90095 USA

来源：

DEVELOPMENTAL CELL | 2013年 / 25卷 / 01期

关键词：

PLURIPOTENT STEM-CELLS; DISULFIDE BOND FORMATION; INTERMEMBRANE SPACE PROTEINS; DEPENDENT SULFHYDRYL OXIDASE; CYTOCHROME-C; LIVER-REGENERATION; ADP/ATP CARRIER; ELECTRON-TRANSFER; IMPORT PATHWAY; RELAY SYSTEM;

D O I：

10.1016/j.devcel.2013.03.006

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

The mitochondrial disulfide relay system of Mia40 and Erv1/ALR facilitates import of the small translocase of the inner membrane (Tim) proteins and cysteine-rich proteins. A chemical screen identified small molecules that inhibit Erv1 oxidase activity, thereby facilitating dissection of the disulfide relay system in yeast and vertebrate mitochondria. One molecule, mitochondrial protein import biockers from the Carla Koehler laboratory (MitoBloCK-6), attenuated the import of Erv1 substrates into yeast mitochondria and inhibited oxidation of Tim13 and Cmc1 in in vitro reconstitution assays. In addition, MitoBloCK-6 revealed an unexpected role for Erv1 in the carrier import pathway, namely transferring substrates from the translocase of the outer membrane complex onto the small Tim complexes. Cardiac development was impaired in MitoBloCK-6-exposed zebrafish embryos. Finally, MitoBloCK-6 induced apoptosis via cytochrome c release in human embryonic stem cells (hESCs) but not in differentiated cells, suggesting an important role for ALR in hESC homeostasis.

引用

页码：81 / 92

页数：12

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