Abstract
The transfer of Ca(2+) across the inner mitochondrial membrane is an important physiological process linked to the regulation of metabolism, signal transduction, and cell death. While the definite molecular composition of mitochondrial Ca(2+) uptake sites remains unknown, several proteins of the inner mitochondrial membrane, that are likely to accomplish mitochondrial Ca(2+) fluxes, have been described: the novel uncoupling proteins 2 and 3, the leucine zipper-EF-hand containing transmembrane protein 1 and the mitochondrial calcium uniporter. It is unclear whether these proteins contribute to one unique mitochondrial Ca(2+) uptake pathway or establish distinct routes for mitochondrial Ca(2+) sequestration. In this study, we show that a modulation of Ca(2+) release from the endoplasmic reticulum by inhibition of the sarco/endoplasmatic reticulum ATPase modifies cytosolic Ca(2+) signals and consequently switches mitochondrial Ca(2+) uptake from an uncoupling protein 3- and mitochondrial calcium uniporter-dependent, but leucine zipper-EF-hand containing transmembrane protein 1-independent to a leucine zipper-EF-hand containing transmembrane protein 1- and mitochondrial calcium uniporter-mediated, but uncoupling protein 3-independent pathway. Thus, the activity of sarco/endoplasmatic reticulum ATPase is significant for the mode of mitochondrial Ca(2+) sequestration and determines which mitochondrial proteins might actually accomplish the transfer of Ca(2+) across the inner mitochondrial membrane. Moreover, our findings herein support the existence of distinct mitochondrial Ca(2+) uptake routes that might be essential to ensure an efficient ion transfer into mitochondria despite heterogeneous cytosolic Ca(2+) rises.
Highlights
Mitochondria may utilize different proteins to decode high and low cytosolic Ca2ϩ
The time gap between the histamine induced rise of [Ca2ϩ]cyto and the respective mitochondrial Ca2ϩ signal was considerably extended in the presence of thapsigargin (Fig. 1, B & C), indicating that sarco/endoplasmatic reticulum ATPase (SERCA) inhibition decelerates the transfer of Ca2ϩ into mitochondria upon IP3mediated Ca2ϩ release
These findings demonstrated that in protocols in which SERCA was blocked after the initiation of IP3-mediated Ca2ϩ release, mitochondrial Ca2ϩ uptake switched from an UCP3-reliant to a leucine zipper-EF-hand containing transmembrane protein 1 (Letm1)-dependent mode
Summary
Mitochondria may utilize different proteins to decode high and low cytosolic Ca2ϩ. Results: Inhibition of SERCA shifts mitochondrial Ca2ϩ uptake from being UCP3-dependent to Letm1-dependent. While the definite molecular composition of mitochondrial Ca2؉ uptake sites remains unknown, several proteins of the inner mitochondrial membrane, that are likely to accomplish mitochondrial Ca2؉ fluxes, have been described: the novel uncoupling proteins 2 and 3, the leucine zipper-EF-hand containing transmembrane protein 1 and the mitochondrial calcium uniporter It is unclear whether these proteins contribute to one unique mitochondrial Ca2؉ uptake pathway or establish distinct routes for mitochondrial Ca2؉ sequestration. In the same cell types, the novel uncoupling proteins 2 and 3 (UCP2/3) were found to contribute primarily to the instant transfer of intracellularly released Ca2ϩ into mitochondria while UCP2/3 did not appear to be engaged in mitochondrial Ca2ϩ uptake upon activation of SOCE (17– 19) Such distinct contribution of Letm and UCP2/3 to mitochondrial Ca2ϩ uptake might explain the versatility of mitochondria to decode the various patterns of the cytosolic Ca2ϩ signal (20), while the actual molecular function of these proteins remain elusive (6, 21). This technique allowed us to follow simultaneously respective Ca2ϩ signals in both compartments
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