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

In addition to their well-known functions in cellular energy transduction, mitochondria play an important role in modulating the amplitude and time co urse 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 dy namics. Here we describe the functional interaction of mitochondria with st ore-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 mit ochondrial Ca2+ uptake by compounds that dissipate the intramitochondrial p otential unmasks Ca2+-dependent inactivation of I-CRAC. Thus, functional mi tochondria are required to maintain CRAC-channel activity, most likely by p reventing local Ca2+ accumulation near sites that govern channel inactivati on. In cells stimulated through the T-cell antigen receptor, acute blockade of mitochondrial Ca2+ uptake inhibits the nuclear translocation of the tra nscription factor NFAT in parallel with CRAC channel activity and [Ca2+](i) elevation. indicating a functional link between mitochondrial regulation o f I-CRAC and T-cell activation. These results demonstrate a role for mitoch ondria in controlling Ca2+ channel activity and signal transmission from th e plasma membrane to the nucleus.