VEGF stimulation of mitochondrial biogenesis: requirement of AKT3 kinase.
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.
Department of Cell Biology and Anatomy, Medical University of South Carolina, Charleston, SC 29425, USA.
Gary L
GL
Wright
Ioanna G
IG
Maroulakou
Juanita
J
Eldridge
Tiera L
TL
Liby
Vijayalakshmi
V
Sridharan
Philip N
PN
Tsichlis
Robin C
RC
Muise-Helmericks
D000818:Animals; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology*
D006360:Heat-Shock Proteins; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; C491754:AKT3 protein, human; D051057:Proto-Oncogene Proteins c-akt