期刊
JOURNAL OF CELL SCIENCE
卷 123, 期 15, 页码 2553-2564出版社
COMPANY OF BIOLOGISTS LTD
DOI: 10.1242/jcs.070151
关键词
Capacitative Ca2+ entry; ER Ca2+ release; Mitochondrial Ca2+ uniporter; Mitochondrial motility; NCXmito; Pericam; SOCE; Stromal interacting molecule; Calcium
类别
资金
- Austrian Science Funds (FWF) [P20181-B05, 21857-B18, F3010-B05]
- Austrian ministry of education, science and culture
- Austrian Science Fund (FWF) [P 21857] Funding Source: researchfish
- Austrian Science Fund (FWF) [P20181] Funding Source: Austrian Science Fund (FWF)
Store-operated Ca2+ entry (SOCE) is established by formation of subplasmalemmal clusters of the endoplasmic reticulum (ER) protein, stromal interacting molecule 1 (STIM1) upon ER Ca2+ depletion. Thereby, STIM1 couples to plasma membrane channels such as Orai1. Thus, a close proximity of ER domains to the plasma membrane is a prerequisite for SOCE activation, challenging the concept of local Ca2+ buffering by mitochondria as being essential for SOCE. This study assesses the impact of mitochondrial Ca2+ handling and motility on STIM1-Orai1-dependent SOCE. High-resolution microscopy showed only 10% of subplasmalemmal STIM1 clusters to be colocalized with mitochondria. Impairments of mitochondrial Ca2+ handling by inhibition of mitochondrial Na+-Ca2+ exchanger (NCXmito) or depolarization only partially suppressed Ca2+ entry in cells overexpressing STIM1-Orai1. However, SOCE was completely abolished when both NCXmito was inhibited and the inner mitochondrial membrane was depolarized, in STIM1- and Orai1-overexpressing cells. Immobilization of mitochondria by expression of mAKAP-RFP-CAAX, a construct that physically links mitochondria to the plasma membrane, affected the Ca2+ handling of the organelles but not the activity of SOCE. Our observations indicate that mitochondrial Ca2+ uptake, including reversal of NCXmito, is fundamental for STIM1-Orai1-dependent SOCE, whereas the proximity of mitochondria to STIM1-Orai1 SOCE units and their motility is not required.
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