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Uncoupling protein 2 impacts endothelial phenotype via p53-mediated control of mitochondrial dynamics.

ABSTRACT: 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.To determine how mitochondria impact endothelial cell function.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 (??) 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.These data identify a novel mechanism whereby mitochondria preserve normal network integrity and impact cell phenotype via dynamic regulation of UCP2.

SUBMITTER: Shimasaki Y

PROVIDER: S-EPMC3869454 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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Uncoupling protein 2 impacts endothelial phenotype via p53-mediated control of mitochondrial dynamics.

Shimasaki Yukio Y Pan Ning N Messina Louis M LM Li Chunying C Chen Kai K Liu Lijun L Cooper Marcus P MP Vita Joseph A JA Keaney John F JF

Circulation research 20130702 7

<h4>Rationale</h4>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.<h4>Objective</h4>To determine how mitochondria impact endothelial cell function.<h4>Methods and results</h4>We report here that stimuli for endothelial cell proliferation evoke strong upregulation of mitochond ...[more]

PMID: 23819990

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Project description:Diabetic complications are the leading cause of morbidity and mortality in diabetic patients. Elevated blood glucose contributes to the development of endothelial and vascular dysfunction, and, consequently, to diabetic micro- and macrovascular complications, because it increases the mitochondrial proton gradient and mitochondrial oxidant production. Therapeutic approaches designed to counteract glucose-induced mitochondrial reactive oxygen species (ROS) production in the vasculature are expected to show efficacy against all diabetic complications, but direct pharmacological targeting (scavenging) of mitochondrial oxidants remains challenging due to the high reactivity of some of these oxidant species. In a recent study, we have conducted a medium-throughput cell-based screening of a focused library of well-annotated pharmacologically active compounds and identified glucocorticoids as inhibitors of mitochondrial superoxide production in microvascular endothelial cells exposed to elevated extracellular glucose. The goal of the current study was to investigate the mechanism of glucocorticoids' action. Our findings show that glucocorticoids induce the expression of the mitochondrial UCP2 protein and decrease the mitochondrial potential. UCP2 silencing prevents the protective effect of the glucocorticoids on ROS production. UCP2 induction also increases the oxygen consumption and the "proton leak" in microvascular endothelial cells. Furthermore, glutamine supplementation augments the effect of glucocorticoids via further enhancing the expression of UCP2 at the translational level. We conclude that UCP2 induction represents a novel experimental therapeutic intervention in diabetic vascular complications. While direct repurposing of glucocorticoids may not be possible for the therapy of diabetic complications due to their significant side effects that develop during chronic administration, the UCP2 pathway may be therapeutically targetable by other, glucocorticoid-independent pharmacological means.

Dataset Information

Uncoupling protein 2 impacts endothelial phenotype via p53-mediated control of mitochondrial dynamics.

Publications

Uncoupling protein 2 impacts endothelial phenotype via p53-mediated control of mitochondrial dynamics.

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