Unknown

Dataset Information

0

AKT3 controls mitochondrial biogenesis and autophagy via regulation of the major nuclear export protein CRM-1.


ABSTRACT: Our previous work has shown that Akt3 is required for mitochondrial biogenesis in primary human endothelial cells (ECs) and in Akt3-null mice; Akt3 affects subcellular localization of peroxisome proliferator-activated receptor ? coactivator-1 (PGC-1?), the master regulator of mitochondrial biogenesis. The purpose of this study is to determine the mechanism by which Akt3 controls the subcellular distribution of PGC-1? and to explore the effect on mitochondrial biogenesis and turnover during angiogenesis. Here we use standard biochemical analyses and Akt3-knockdown strategies to show that Akt3 controls the stabilization of chromosome maintenance region-1 (CRM-1), the major nuclear export receptor. Site-directed mutagenesis and association analyses show that PGC-1? nuclear export is CRM-1 dependent. Akt3 knockdown and CRM-1 overexpression cause 3-fold reductions in PGC-1? target gene expression, compared to control levels. Akt3 inhibition causes autophagy, as measured by autophagosome formation, in a CRM-1-dependent, Akt1/mTOR-independent pathway. In vivo, Akt3-null and heterozygous mice show dose-dependent decreases in angiogenesis compared to wild-type littermates (~5- and 2.5-fold decreases, respectively), as assessed by Matrigel plug assays. This correlates with an ~1.5-fold decrease in mitochondrial Cox IV expression. Our studies suggest that Akt3 is a regulator of mitochondrial dynamics in the vasculature via regulation of CRM-1-dependent nuclear export.

SUBMITTER: Corum DG 

PROVIDER: S-EPMC3868834 | biostudies-other | 2014 Jan

REPOSITORIES: biostudies-other

altmetric image

Publications

AKT3 controls mitochondrial biogenesis and autophagy via regulation of the major nuclear export protein CRM-1.

Corum Daniel G DG   Tsichlis Philip N PN   Muise-Helmericks Robin C RC  

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20130930 1


Our previous work has shown that Akt3 is required for mitochondrial biogenesis in primary human endothelial cells (ECs) and in Akt3-null mice; Akt3 affects subcellular localization of peroxisome proliferator-activated receptor γ coactivator-1 (PGC-1α), the master regulator of mitochondrial biogenesis. The purpose of this study is to determine the mechanism by which Akt3 controls the subcellular distribution of PGC-1α and to explore the effect on mitochondrial biogenesis and turnover during angio  ...[more]

Similar Datasets

| S-EPMC151917 | biostudies-literature
| S-EPMC6098152 | biostudies-literature
| S-EPMC6220341 | biostudies-literature
| S-EPMC4999898 | biostudies-literature
| S-EPMC5602412 | biostudies-literature
| S-EPMC4744108 | biostudies-literature
| S-EPMC8739877 | biostudies-literature
| S-EPMC7007576 | biostudies-literature
| S-EPMC5203823 | biostudies-literature