VEGF stimulation of mitochondrial biogenesis: requirement of AKT3 kinase

Abstract

The growth factor, vascular endothelial growth factor (VEGF), induces angiogenesis and promotes endothelial cell (EC) proliferation. Affymetrix gene array analyses show that VEGF stimulates the expression of a cluster of nuclear-encoded mitochondrial genes, suggesting a role for VEGF in the regulation of mitochondrial biogenesis. We show that the serine threonine kinase Akt3 specifically links VEGF to mitochondrial biogenesis. A direct comparison of Akt1 vs. Akt3 gene silencing was performed in ECs and has uncovered a discrete role for Akt3 in the control of mitochondrial biogenesis. Silencing of Akt3, but not Akt1, results in a decrease in mitochondrial gene expression and mtDNA content. Nuclear-encoded mitochondrial gene transcripts are also found to decrease when Akt3 expression is silenced. Concurrent with these changes in mitochondrial gene expression, lower O(2) consumption was observed. VEGF stimulation of the major mitochondrial import protein TOM70 is also blocked by Akt3 inhibition. In support of a role for Akt3 in the regulation of mitochondrial biogenesis, Akt3 silencing results in the cytoplasmic accumulation of the master regulator of mitochondrial biogenesis, PGC-1alpha, and a reduction in known PGC-1alpha target genes. Finally, a subtle but significant, abnormal mitochondrial phenotype is observed in the brain tissue of AKT3 knockout mice. These results suggest that Akt3 is important in coordinating mitochondrial biogenesis with growth factor-induced increases in cellular energy demands.

Regulation of VEGF-induced endothelial cell migration by mitochondrial reactive oxygen species

“…Interestingly, new studies using gene expression analysis show that VEGF stimulation increases mitochondrial biogenesis to meet higher cellular energy demands (50). Consistent with this observation, we detected VEGF-induced increases in mitochondrial metabolism and mtROS production.…”

“…Mitochondrial oxidants regulate VEGF receptor transactivation and redox-dependent downstream signaling (10), promote endothelial sprouting (12), and stimulate NF-B and TNF-␣-induced apoptosis (23). A recent study showed that VEGF stimulates mitochondrial gene expression in endothelial cells, thereby implicating VEGF in the regulation of mitochondrial biogenesis (50). However, the role of endothelial mtROS during VEGF-induced cell signaling is still unclear.…”

Redox Regulation of Mitochondrial Function

“…It is well known that redoxinactivation of PTEN plays an important role in allowing phosphatidylinositol-3,4,5-triphosphate (PIP3) accumulation in the cell membrane to recruit PDK1 and Akt as part of the PDK1-mediated phosphorylation of Akt (269). In some cell types, Akt3, rather than Akt1, may play a role in growth factor-mediated stimulation of biogenic pathways (455), and other studies identify a role for Akt pathways in the heme oxygenase-mediated modulation of biogenesis, which involves oxidant activation of NRF1 transcription via antioxidant response elements in the NRF1 promoter (329).…”

Angiogenesis revisited – role and therapeutic potential of targeting endothelial metabolism

“…VEGF has been shown to activate one of the master regulators of mitochondrial biogenesis and oxidative metabolism, peroxisome proliferator-activated receptor-c coactivator1a (PGC-1a; encoded by the gene PPARGC1A), leading to increased mitochondrial biogenesis in endothelial and other cell types (Arany et al, 2008;Wright et al, 2008). PGC-1a expression in heart and muscle cells induces angiogenesis, implying that PGC1a stimulates vascularization and prepares ischemic tissues for oxidative metabolism that is permitted by improved oxygenation.…”