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VEGF stimulation of mitochondrial biogenesis: requirement of AKT3 kinase

Gary L. Wright, Ioanna G. Maroulakou, Juanita Eldridge^*, Tiera L. Liby^*, Vijayalakshmi Sridharan, Philip N. Tsichlis and Robin C. Muise-Helmericks^*,1

^* Department of Cell Biology and Anatomy and

Department of Pharmaceutical Sciences, Medical University of South Carolina, Charleston, South Carolina, USA; and

Molecular Oncology Research Institute, Tufts-New England Medical Center, Boston, Massachusetts, USA

¹ Correspondence: Medical University of South Carolina, Hollings Cancer Center Rm 320, 86 Jonathan Lucas St., Charleston, SC 29425, USA. E-mail: musehelm{at}musc.edu

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 O₂ 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-1, and a reduction in known PGC-1 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.—Wright, G. L., Maroulakou, I. G., Eldridge, J., Liby, T. L., Sridharan, V., Tsichlis, P. N., Muise-Helmericks, R. C. VEGF stimulation of mitochondrial biogenesis: requirement of AKT3 kinase.

Key Words: angiogenesis • VEGF signal transduction • Akt kinase • PGC-1 • mitochondrial protein import