Mitochondrial ATP production provides long-range control of endothelial inositol trisphosphate–evoked calcium signaling : mitochondrial control of endothelial Ca2+ signaling

Wilson, Calum and Lee, Matthew D. and Heathcote, Helen R. and Zhang, Xun and Buckley, Charlotte and Girkin, John M. and Saunter, Christopher D. and McCarron, John G. (2019) Mitochondrial ATP production provides long-range control of endothelial inositol trisphosphate–evoked calcium signaling : mitochondrial control of endothelial Ca2+ signaling. Journal of Biological Chemistry, 294 (3). pp. 737-758. ISSN 1083-351X

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    Abstract

    Endothelial cells are reported to be glycolytic and to minimally rely on mitochondria for ATP generation. Rather than providing energy, mitochondria in endothelial cells may act as signaling organelles that control cytosolic Ca2+ signaling or modify reactive oxygen species (ROS). To control Ca2+ signaling, these organelles are often observed close to influx and release sites and may be tethered near Ca2+ transporters. In this study, we used high-resolution, wide-field fluorescence imaging to investigate the regulation of Ca2+ signaling by mitochondria in large numbers of endothelial cells (~50 per field) in intact arteries from rats. We observed that mitochondria were mostly spherical or short-rod structures and were distributed widely throughout the cytoplasm. The density of these organelles did not increase near contact sites with smooth muscle cells. However, local inositol trisphosphate (IP3)-mediated Ca2+ signaling predominated near these contact sites and required polarized mitochondria. Of note, mitochondrial control of Ca2+ signals occurred even when mitochondria were far from Ca2+ release sites. Indeed, the endothelial mitochondria were mobile and moved throughout the cytoplasm. Mitochondrial control of Ca2+ signaling was mediated by ATP production, which, when reduced by mitochondrial depolarization or ATP synthase inhibition, eliminated local IP3-mediated Ca2+ release events. ROS buffering did not significantly alter local Ca2+ release events. These results highlight the importance of mitochondrial ATP production in providing long-range control of endothelial signaling via IP3-evoked local Ca2+ release in intact endothelium