Endoplasmic reticulum Ca2+ release causes Rieske iron–sulfur protein-mediated mitochondrial ROS generation in pulmonary artery smooth muscle cells. Issue 12 (4th December 2019)

• Record Type: Journal Article
• Authors: Dong, Dapeng; Hao, Qiongyu; Zhang, Ping; Wang, Tao; Han, Fei; Liang, Xiaodong; Fei, Zhenghua
• Is Part Of: Bioscience reports. Volume 39:Issue 12(2019)
• Publication Date: 2019-12-04
• Subjects: Intracellular calcium -- mitochondrial ROS -- Ryanodine receptor; Molecular biology -- Periodicals; Cytology -- Periodicals; 572.8
• DOI: 10.1042/BSR20192414
• Languages: English
• ISSNs: 0144-8463

Abstract

Abstract: Mitochondrial reactive oxygen species (ROS) cause Ca 2+ 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 Ca 2+ 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 Ca 2+ concentration ([Ca 2+ ]i ) by activating RyRs results in a significant increase in ROS production in cytosol and mitochondria of PASMCs. Norepinephrine to increase [Ca 2+ ]i due to the opening of inositol 1, 4, 5-triphosphate receptors (IP3Rs) produces similar effects. Exogenous Ca 2+ 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 Ca 2+ uptake with Ru360 eliminates N- and Ca 2+ -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 Ca 2+ release causes mitochondrial Ca 2+ uptake and RISP-mediated ROS production; this novel local ER/mitochondrion communication-elicited, Ca 2+ -mediated, RISP-dependent ROS production may play a significant role in hypoxic cellular responses in PASMCs.