Endoplasmic reticulum Ca2+ release causes Rieske iron–sulfur protein-mediated mitochondrial ROS generation in pulmonary artery smooth muscle cells
Authors: Tao Wang
Dapeng Dong
Fei Han
Zhenghua Fei
Ping Zhang
Qiongyu Hao
Xiaodong Liang
Journal: Bioscience Reports (2019)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: Intracellular calcium; Ryanodine receptor; mitochondrial ROS.
Affiliations: Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China., Division of Cancer Research and Training, Department of Internal Medicine, Charles Drew University of Medicine and Science, Los Angeles, CA 90059, U.S.A., David Geffen UCLA School of Medicine and UCLA Jonsson Comprehensive Cancer Center, Los Angeles, CA 90095, U.S.A., Radiation and Medical Oncology Department, The 1st Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China., The Key Laboratory of Urinary Tract Tumors and Calculi, Department of Urology Surgery, The First Affiliated Hospital of Xiamen University, Xiamen 361003, China., Division of Radiological Sciences, Washington University School of Medicine in Saint Louis, MO 63110, U.S.A., Department of Pathology, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China., Department of Pathology, Yancheng Hospital Affiliated Southeast University, Yancheng, Jiangsu 224000, China.

Abstract:  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. 

Retracted: Yes

PubPeer comments:
 2020 retraction. https: portlandpress.com bioscirep article 40 4 BSR-20192414_RET 222746 Retraction-Endoplasmic-reticulum-Ca2-release RETRACTION| APRIL 23 2020 Retraction: Endoplasmic reticulum Ca2+ release causes rieske iron-sulfur protein-mediated mitochondrial ROS generation in pulmonary artery smooth muscle cells Biosci Rep (2020) 40 (4): BSR-20192414_RET. https: doi.org 10.1042 BSR-20192414_RET Connected Content retraction: Endoplasmic reticulum Ca2+ release causes Rieske ironu2013sulfur protein-mediated mitochondrial ROS generation in pulmonary artery smooth muscle cells Split-Screen PDF Link PDF Share Icon Share Cite Icon Cite Get Permissions Keywords:Intracellular calcium, mitochondrial ROS, Ryanodine receptor The authors of the following paper u201cEndoplasmic Reticulum Ca2+ Release Causes Rieske Iron-Sulfur Protein-mediated Mitochondrial ROS Generation in Pulmonary Artery Smooth Muscle Cellsu201d (Bioscience Reports (2019) 39(12) https: doi.org 10.1042 BSR20192414) would like to retract their paper. They have provided the following justification for retraction: The results in the published paper indicated that mitochondrial ROS generation was increased by hypoxia treatment (see Figure 4A). Inhibition of RyRs with tetracaine or genetic deletion of RyR2 attenuated hypoxia-induced ROS generation in mitochondria (see Figure 4A,B). However, the authors have been unable to repeat the results in subsequent experiments, and their latest data have shown that deprivation of RyR2 is not able to attenuate hypoxia-induced ROS generation in mitochondria. All authors agree to the retraction, and apologise for any misunderstanding caused by their results. ,