JOURNAL ARTICLE
RESEARCH SUPPORT, NON-U.S. GOV'T
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Intact mitochondrial Ca 2+ uniport is essential for agonist-induced activation of endothelial nitric oxide synthase (eNOS).

Mitochondrial Ca2+ uptake regulates diverse endothelial cell functions and has also been related to nitric oxide (NO• ) production. However, it is not entirely clear if the organelles support or counteract NO• biosynthesis by taking up Ca2+ . The objective of this study was to verify whether or not mitochondrial Ca2+ uptake influences Ca2+ -triggered NO• generation by endothelial NO• synthase (eNOS) in an immortalized endothelial cell line (EA.hy926), respective primary human umbilical vein endothelial cells (HUVECs) and eNOS-RFP (red fluorescent protein) expressing human embryonic kidney (HEK293) cells. We used novel genetically encoded fluorescent NO• probes, the geNOps, and Ca2+ sensors to monitor single cell NO• and Ca2+ dynamics upon cell treatment with ATP, an inositol 1,4,5-trisphosphate (IP3 )-generating agonist. Mitochondrial Ca2+ uptake was specifically manipulated by siRNA-mediated knock-down of recently identified key components of the mitochondrial Ca2+ uniporter machinery. In endothelial cells and the eNOS-RFP expressing HEK293 cells we show that reduced mitochondrial Ca2+ uptake upon the knock-down of the mitochondrial calcium uniporter (MCU) protein and the essential MCU regulator (EMRE) yield considerable attenuation of the Ca2+ -triggered NO• increase independently of global cytosolic Ca2+ signals. The knock-down of mitochondrial calcium uptake 1 (MICU1), a gatekeeper of the MCU, increased both mitochondrial Ca2+ sequestration and Ca2+ -induced NO• signals. The positive correlation between mitochondrial Ca2+ elevation and NO• production was independent of eNOS phosphorylation at serine1177 . Our findings emphasize that manipulating mitochondrial Ca2+ uptake may represent a novel strategy to control eNOS-mediated NO• production.

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