Uncoupling protein 2 impacts endothelial phenotype via p53-mediated control of mitochondrial dynamics
Department of Medicine, Division of Cardiovascular Medicine; Department of Surgery, Division of Vascular Surgery
Animals; Aorta; Cattle; Cell Aging; Cell Proliferation; Endothelial Cells; Ion Channels; Lung; Membrane Potential, Mitochondrial; Mice; Mitochondria; *Mitochondrial Dynamics; Mitochondrial Proteins; *Phenotype; Superoxides; Tumor Suppressor Protein p53; Up-Regulation
Cell Biology | Cellular and Molecular Physiology
RATIONALE: Mitochondria, although required for cellular ATP production, are also known to have other important functions that may include modulating cellular responses to environmental stimuli. However, the mechanisms whereby mitochondria impact cellular phenotype are not yet clear.
OBJECTIVE: To determine how mitochondria impact endothelial cell function.
METHODS AND RESULTS: We report here that stimuli for endothelial cell proliferation evoke strong upregulation of mitochondrial uncoupling protein 2 (UCP2). Analysis in silico indicated increased UCP2 expression is common in highly proliferative cell types, including cancer cells. Upregulation of UCP2 was critical for controlling mitochondrial membrane potential (Deltapsi) and superoxide production. In the absence of UCP2, endothelial growth stimulation provoked mitochondrial network fragmentation and premature senescence via a mechanism involving superoxide-mediated p53 activation. Mitochondrial network fragmentation was both necessary and sufficient for the impact of UCP2 on endothelial cell phenotype.
CONCLUSIONS: These data identify a novel mechanism whereby mitochondria preserve normal network integrity and impact cell phenotype via dynamic regulation of UCP2.
DOI of Published Version
Circ Res. 2013 Sep 13;113(7):891-901. doi: 10.1161/CIRCRESAHA.113.301319. Epub 2013 Jul 2. Link to article on publisher's site
Shimasaki, Yukio; Pan, Ning; Messina, Louis M.; Li, Chunying; Chen, Kai; Liu, Lijun; Cooper, Marcus P.; Vita, Joseph A.; and Keaney, John F. Jr., "Uncoupling protein 2 impacts endothelial phenotype via p53-mediated control of mitochondrial dynamics" (2013). University of Massachusetts Medical School Faculty Publications. 606.