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 Ca²⁺ signals. In many cells, mitochondria act as Ca²⁺ buffers by taking up and releasing Ca²⁺, but this simple buffering action by itself often cannot explain the organelle's effects on Ca²⁺ signaling dynamics. Here we describe the functional interaction of mitochondria with store-operated Ca²⁺ channels in T lymphocytes as a mechanism of mitochondrial Ca²⁺ signaling. In Jurkat T cells with functional mitochondria, prolonged depletion of Ca²⁺ stores causes sustained activation of the store-operated Ca²⁺ current, I_CRAC (CRAC, Ca²⁺ release-activated Ca²⁺). Inhibition of mitochondrial Ca²⁺ uptake by compounds that dissipate the intramitochondrial potential unmasks Ca²⁺-dependent inactivation of I_CRAC. Thus, functional mitochondria are required to maintain CRAC-channel activity, most likely by preventing local Ca²⁺ accumulation near sites that govern channel inactivation. In cells stimulated through the T-cell antigen receptor, acute blockade of mitochondrial Ca²⁺ uptake inhibits the nuclear translocation of the transcription factor NFAT in parallel with CRAC channel activity and [Ca²⁺]_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 Ca²⁺ channel activity and signal transmission from the plasma membrane to the nucleus.