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Store-operated Ca2+ influx and subplasmalemmal mitochondria
Authors:Marek K. Korzeniowski  Gergö Szanda  Tamas Balla  András Spät
Affiliation:1. Section on Molecular Signal Transduction, Program on Developmental Neuroscience, NICHD, NIH, Bethesda, MD, USA;2. Dept. of Physiology, Semmelweis University, Budapest, Hungary;3. Laboratory of Neurobiochemistry and Molecular Physiology, Hungarian Academy of Sciences, Budapest, Hungary;1. Cardiovascular Division, Zhejiang Province People?s Hospital, 158 Shangtang Road, Hangzhou 310014, PR China;2. Cardiovascular Division, Jiaxing No. 2 Hospital, 1882 Central Circle Road South, Jiaxing 314001, PR China;3. Chinese Herb Medicine Division, The Nurturing Station for the State Key Laboratory of Subtropical Silviculture, Zhejiang Agriculture and Forestry University, 88 North Circle Road, Lin’an 311300, PR China;4. Safety Pharmacology Division, Olivepharmasolutions Ltd., 333 Changhong Road, Wukang 313200, PR China;5. Pathophysiolog department, Medical School, Zhejiang University, Hangzhou 310058, PR China;1. State Key Laboratory of Cancer Biology, Department of Medical Genetics and Developmental Biology, The Fourth Military Medical University, Xi''an, 710032, China;2. Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi''an, 710032, China;1. Department of Chemical and Biomedical Engineering, University of South Florida, Tampa, FL, USA;2. Global Center of Speech and Hearing Research, University of South Florida, Tampa, FL, USA;3. School of Nursing, University of Rochester, Rochester, NY, USA;4. Department of Physics, University of South Florida, Tampa, FL, USA;5. Department of Communication Sciences and Disorders, University of South Florida, Tampa, FL, USA;1. Institute of Molecular Biology and Biochemistry, Center of Molecular Medicine, Medical University of Graz, Harrachgasse 21/III, 8010 Graz, Austria;3. Department of Physiology and Biophysics, Weill Cornell Medical College in Qatar, Qatar Foundation, Education City, Doha 24144, Qatar;4. Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205;5. Department of Biological and Environmental Sciences, Qatar University, Doha 2713, Qatar
Abstract:Calcium depletion of the endoplasmic reticulum (ER) induces oligomerisation, puncta formation and translocation of the ER Ca2+ sensor proteins, STIM1 and -2 into plasma membrane (PM)-adjacent regions of the ER, where they activate the Orai1, -2 or -3 proteins present in the opposing PM. These proteins form ion channels through which store-operated Ca2+ influx (SOC) occurs. Calcium ions exert negative feed-back on SOC. Here we examined whether subplasmalemmal mitochondria, which reduce this feed-back by Ca2+ uptake, are located within or out of the high-Ca2+ microdomains (HCMDs) formed between the ER and plasmalemmal Orai1 channels. For this purpose, COS-7 cells were cotransfected with Orai1, STIM1 labelled with YFP or mRFP and the mitochondrially targeted Ca2+ sensitive fluorescent protein inverse-Pericam. Depletion of ER Ca2+ with ATP + thapsigargin (in Ca2+-free medium) induced the appearance of STIM1 puncta in the ≤100 nm wide subplasmalemmal space, as examined with TIRF. Mitochondria were located either in the gaps between STIM1-tagged puncta or in remote, STIM1-free regions. After addition of Ca2+ mitochondrial Ca2+ concentration increased irrespective of the mitochondrion–STIM1 distance. These observations indicate that mitochondria are exposed to Ca2+ diffused laterally from the HCMDs formed between the PM and the subplasmalemmal ER.
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