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.