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 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 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-1α nuclear export is CRM-1 dependent. Akt3 knockdown and CRM-1 overexpression cause 3-fold reductions in PGC-1α 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.

Genomically amplified Akt3 activates DNA repair pathway and promotes glioma progression

“…Additional studies are reporting potential nuclear functions of Akt3, including Ago2-mediated translational repressive activities (28), transcriptional control of IGFBP3 in lung cancer cells (29), and ERBB2, ERBB3, and ERα in breast tumor cells from a mouse transgenic model (30). Although these effects are likely mediated by multiple complex systems, Akt3 has been reported to control the stability of the major nuclear export protein, chromosome maintenance region-1 (CRM-1), leading to altered mitochondrial biogenesis and autophagy (31). It is plausible that Akt3 may regulate other biological processes via similar mechanisms.…”

Akt1 and Akt3 Exert Opposing Roles in the Regulation of Vascular Tumor Growth

“…Limited studies on Akt3 showed that it is required for VEGF stimulation of mitochondrial biogenesis and autophagy in endothelial cell, and is important for growth-factor induced angiogenic responses (32). Akt3 is the dominant isoform in melanoma and ovarian cancer and regulates cellular senescence, VEGF secretion and angiogenesis in these tumors (33)(34)(35).…”

Role of regeneration in tissue repairing and therapies

“…Stem cells also help in dental cares by inducing regeneration or differentiation of dental epithelia into enamel-producing ameloblasts [86]. MSCs implanted in pancreas can replace defective islet beta cells, enhance β-cell proliferation [87], cure type 1 diabetes [88] and do its reversal [89,90,98,99] in non-obese diabetic mice [91,92]. Similarly, implantation of multipotent stem cells implanted in bone marrow can suppress ovarian cancer and stop metastasis [90,92].…”

“…Endothelial cells (ECs) show wider therapeutic potential in cardiovascular [94,95], Parkinson's disease [95,96], and neurological diseases [97]. These cells do immune regulation of T lymphocyte cells [93,98] and induce mitochondrial biogenesis in primary human endothelial cells (ECs) and in Akt3-null mice [89,99]. MSCs are used in regenerative medicine, for wound healing, tissue regeneration and transplantation of organs and therapeutic care of autoimmune diseases ( Table 1).…”

“…Hence, new innovation are needed for development of novel prognostic, diagnostic, and treatment options that may provide major benefits for patients with acute or chronic respiratory dysfunction, cardiac-related disorders, esophageal problems, or other diseases in the thorax. Though, allogeneic organ transplants are also made but these could show very low rates of success because of its dependency on a very limited supply of donated organs [102]. Such organ transplants also require lifelong treatment with immunosuppressants, if these remain unavailable generate many adverse effects.…”