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Pivotal role of mitochondrial Na⁺₋Ca²⁺ exchange in antigen receptor mediated Ca²⁺ signalling in DT40 and A20 B lymphocytes

, : Pivotal role of mitochondrial Na⁺₋Ca²⁺ exchange in antigen receptor mediated Ca²⁺ signalling in DT40 and A20 B lymphocytes. Journal of Physiology 590(3): 459-474

Cytoplasmic Ca(2+) concentration ([Ca(2+)](i)) increases upon activation of antigen-receptor in lymphocytes. Mitochondria have been suggested to regulate the [Ca(2+)](i) response, but the molecular mechanisms and the roles are poorly understood. To clarify them, we carried out a combination study of mathematical simulations and knockout or knockdown of NCLX, a gene candidate for the mitochondrial Na(+)-Ca(2+) exchanger (NCX(mit)), in B lymphocytes. A mathematical model of Ca(2+) dynamics in B lymphocytes demonstrated that NCX(mit) inhibition reduces basal Ca(2+) content of endoplasmic reticulum (ER) and suppresses B-cell antigen receptor (BCR)-mediated [Ca(2+)](i) rise. The predictions were validated in DT40 B lymphocytes of heterozygous NCLX knockout (NCLX(+/-)). In NCLX(+/-) cells, mitochondrial Ca(2+) efflux via NCX(mit) was strongly decelerated, suggesting NCLX is a gene responsible for NCX(mit) in B lymphocytes. Consistent with the predictions, ER Ca(2+) content declined and [Ca(2+)](i) hardly rose upon BCR activation in NCLX(+/-) cells. ER Ca(2+) uptake was reduced to ∼58% of the wild-type (WT), while it was comparable to WT when mitochondrial respiration was disturbed. Essentially the same results were obtained by a pharmacological inhibition or knockdown of NCLX by siRNA in A20 B lymphocytes. Unexpectedly, ER Ca(2+) leak was augmented and co-localization of mitochondria with ER was lower in NCLX(+/-) and NCLX silenced cells. Taken together, we concluded that NCLX is a key Ca(2+) provider to ER, and that NCLX-mediated Ca(2+) recycling between mitochondria and ER is pivotal in B cell responses to antigen.


PMID: 22155933

DOI: 10.1113/jphysiol.2011.222927

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