Mitochondrial control of calcium-channel gating: A mechanism for sustained signaling and transcriptional activation in T lymphocytes

Abstract

In addition to their well-known functions in cellular energy transduction, mitochondria play an important role in modulating the amplitude and time course of intracellular Ca 2+ signals. In many cells, mitochondria act as Ca 2+ buffers by taking up and releasing Ca 2+ , but this simple buffering action by itself often cannot explain the organelle's effects on Ca 2+ signaling dynamics. Here we describe the functional interaction of mitochondria with store-operated Ca 2+ channels in T lymphocytes as a mechanism of mitochondrial Ca 2+ signaling. In Jurkat T cells with functional mitochondria, prolonged depletion of Ca 2+ stores causes sustained activation of the store-operated Ca 2+ current, I CRAC (CRAC, Ca 2+ release-activated Ca 2+ ). Inhibition of mitochondrial Ca 2+ uptake by compounds that dissipate the intramitochondrial potential unmasks Ca 2+ -dependent inactivation of I CRAC . Thus, functional mitochondria are required to maintain CRAC-channel activity, most likely by preventing local Ca 2+ accumulation near sites that govern channel inactivation. In cells stimulated through the T-cell antigen receptor, acute blockade of mitochondrial Ca 2+ uptake inhibits the nuclear translocation of the transcription factor NFAT in parallel with CRAC channel activity and [Ca 2+ ] i elevation, indicating a functional link between mitochondrial regulation of I CRAC and T-cell activation. These results demonstrate a role for mitochondria in controlling Ca 2+ channel activity and signal transmission from the plasma membrane to the nucleus.

TRPC3 Mediates T-cell Receptor-dependent Calcium Entry in Human T-lymphocytes

“…This hypothesis is supported by the finding that TRPC3 channel activity is tightly regulated by the interaction of TRPC3 with both the InsP3 receptor and Ca 2ϩ /calmodulin (24). Furthermore, mitochondrial Ca 2ϩ uptake is likely to regulate Ca 2ϩ entry through TRPC3 channels (49, this study), a mechanism very important for Ca 2ϩ entry through CRAC channels in Tcells (47,48).…”

“…Because it has been shown that Ca 2ϩ channels in T-cells are regulated by mitochondrial Ca 2ϩ uptake (47,48) and that TRPC3 activity depends on functional mitochondria (49), we analyzed the role of mitochondria on TRPC3-dependent Ca 2ϩ entry. Fig.…”

Cyclosporin A-insensitive Permeability Transition in Brain Mitochondria

“…Activation of the mitochondrial PTP may oppose SOCE, based on the fact that SOCE is inhibited by high [Ca 2ϩ ] i and the observation that abolition of Ca 2ϩ uptake by mitochondria inactivates SOCE (77)(78)(79). Thus, it is possible that release of mitochondrial Ca 2ϩ stores through activation of the PTP elevate [Ca 2ϩ ] i , thereby inhibiting SOCE.…”

Bidirectional Ca 2+ -dependent control of mitochondrial dynamics by the Miro GTPase

“…TNF␣-and NGF receptor-activated pathways and plasma membrane phospholipids have been implicated in the control of mitochondrial movements (7)(8)(9)(10). Recently, it has been shown in several cell types that physiological rises of [Ca 2ϩ ] c arrest mitochondrial motility (11)(12)(13)(14), effectively creating a homeostatic feedback circuit that positions these organelles near Ca 2ϩ sources (12) enhancing Ca 2ϩ buffering and ATP production where demand is high (15)(16)(17)(18). Notably, in rat cortical neurons both the presence (11) and absence (19) of sensitivity to Ca 2ϩ was described for mitochondrial motility.…”