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Calcium (Ca2+) is a simple but critical signal for controlling various cellular processes and is especially important in fertilization and embryonic development. The dynamic change of cellular Ca2+ concentration and homeostasis are tightly regulated. Cellular Ca2+ increases by way of Ca2+ influx from extracellular medium and Ca2+ release from cellular stores of the endoplasmic reticulum (ER) and sarcoplasmic reticulum (SR). The elevated Ca2+ is subsequently sequestered by expelling it out of the cell or by pumping back to the ER/SR. Mitochondria function as a power house for energy production via oxidative phosphorylation in most eukaryotes. In addition to this well-known function, mitochondria are also recognized to regulate Ca2+ homeostasis through different mechanisms. Although critical roles of Ca2+ signaling in fertilization and embryonic development are known, the involvement of mitochondria in these processes are not fully understood. This review is focused on the role of mitochondrial respiratory chain complex I in the regulation of Ca2+ signaling pathway and gene expression in embryonic development, especially on the new findings in the cardiac development of Xenopus embryos. The data demonstrate that mitochondria modulate Ca2+ signaling and the Ca2+-dependent NFAT pathway and its target gene which are essential for embryonic heart development.
Fig. 1. Model of Ca2+ signaling and mitochondrial function in heart development. Elevation of [Ca2+]c is elicited by either Ca2+ influx through Ca2+ channels on PM or Ca2+
release from ER/SR via IP3 receptor (IP3R) or ryanodine receptor (RyR). The elevated [Ca2+]c is subsequently sequestered by expelling Ca2+ out of the cell through PMCA pumps
and Na+/Ca2+ exchangers on the PM or by refilling the ER/SR via SERCAs located on the ER/SR membranes. In heart development, non-canonical Wnt proteins may bind to
their G protein-coupled receptor (GPCR), which leads to the activation of PLC and subsequent production of IP3. IP3 binds to the receptor IP3R, which triggers Ca2+ release
from ER. Depletion of the [Ca2+]ER triggers the [Ca2+] influx via CRAC, which is crucial for the activation of the Ca2+- and calmodulin (CaM)-dependent calcineurin. Calcineurin
dephosphorylates NFATc and leads to its nuclear translocation where NFATc associates with its co-transcriptional factor, GATA, and activates the expression of downstream
gene, Nkx2-5. This Ca2+ signaling is tightly controlled by mitochondria. The close proximity between mitochondria and ER facilitates mitochondrial Ca2+ uptake through
uniporter, which activates enzymes of the TCA cycle and promotes ATP production by mitochondrial RC. ATP is in turn exported from mitochondria and consumed by SERCA
which pumps Ca2+ back to ER and rebuilds ER Ca2+ stock. This process is crucial for establishing the potential of the IP3-mediated Ca2+ release. Mitochondria also modulate the
opening of CRAC. The mitochondial Ca2+ uptake near CRAC channels attenuates the negative feedback of Ca2+ on CRAC and prolongs the opening of CRAC. The ATP production
from subplasmalemmal mitochondria also help to maintain the Ca2+ influx through CRAC and facilitates the subsequent activation of the calcineurin–NFAT signaling.
