Endoplasmic Reticulum Ca2+ Release Causes Rieske Iron-Sulfur Protein-mediated Mitochondrial ROS Generation.., 2019, Dong et al

Andy · Nov 13, 2019

Full title: Endoplasmic Reticulum Ca2+ Release Causes Rieske Iron-Sulfur Protein-mediated Mitochondrial ROS Generation in Pulmonary Artery Smooth Muscle Cells

Mitochondrial reactive oxygen species (ROS) cause Ca2+ release from the Endoplasmic reticulum (ER) via ryanodine receptors (RyRs) in pulmonary artery smooth muscle cells (PASMCs), playing an essential role in hypoxic pulmonary vasoconstriction (HPV).

Here we tested a novel hypothesis that hypoxia-induced RyR-mediated Ca2+ release may, in turn, promote mitochondrial ROS generation contributing to hypoxic cellular responses in PASMCs. Our data reveal that application of caffeine to elevate intracellular Ca2+ concentration ([Ca2+]i) by activating RyRs results in a significant increase in ROS production in cytosol and mitochondria of PASMCs. Norepinephrine to increase [Ca2+]i due to the opening of inositol 1,4,5-triphosphate receptors (IP3Rs) produces similar effects. Exogenous Ca2+ significantly increases mitochondrial-derived ROS generation as well. Ru360 also inhibits the hypoxic ROS production. The RyR antagonist tetracaine or RyR2 gene knockout (KO) suppresses hypoxia-induced responses as well. Inhibition of mitochondrial Ca2+ uptake with Ru360 eliminates N- and Ca2+-induced responses. RISP KD abolishes the hypoxia-induced ROS production in mitochondria of PASMCs. Rieske iron-sulfur protein (RISP) gene knockdown (KD) blocks caffeine- or NE-induced ROS production.

Taken together, these findings have further demonstrated that ER Ca2+ release causes mitochondrial Ca2+ uptake and RISP-mediated ROS production; this novel local ER/mitochondrion communication-elicited, Ca2+-mediated, RISP-dependent ROS production may play a significant role in hypoxic cellular responses in PASMCs.
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Open access, https://portlandpress.com/bioscirep...doplasmic-Reticulum-Ca2-Release-Causes-Rieske

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Endoplasmic Reticulum Ca2+ Release Causes Rieske Iron-Sulfur Protein-mediated Mitochondrial ROS Generation.., 2019, Dong et al

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Endoplasmic Reticulum Ca2+ Release Causes Rieske Iron-Sulfur Protein-mediated Mitochondrial ROS Generation.., 2019, Dong et al

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