Chronic Diffuse Interstitial Fibrosis of the Lungs

Ca2+-dependent gene regulation controls many aspects of neuronal plasticity. Significant progress has been made toward understanding the roles of voltage- and ligand-gated Ca2+ channels in triggering specific transcriptional responses. In contrast, the functional importance of Ca2+ buffers and Ca2+ transporters in neuronal gene regulation is less clear despite their critical contribution to the spatiotemporal control of Ca2+ signals. Here we examined the role of mitochondrial Ca2+ uptake and release in regulating the Ca2+-dependent transcription factor NFAT (nuclear factor of activated T-cells), which has been implicated in synaptic plasticity, axonal growth, and neuronal survival. Intense stimulation of sensory neurons by action potentials or TRPV1 agonists induced rapid activation and nuclear import of NFAT. Nuclear translocation of NFAT was associated with a characteristic prolonged [Ca2+]i elevation (plateau) that resulted from Ca2+ uptake by, and its subsequent release from, mitochondria. Measurements using a mitochondrial Ca2+ indicator, mtPericam, showed that this process recruited mitochondria throughout the cell body, including the perinuclear region. [Ca2+]i levels attained during the plateau phase were similar to or higher than those required for NFAT activation (200–300 nm). The elimination of the [Ca2+]i plateau by blocking either mitochondrial Ca2+ uptake via the uniporter or Ca2+ release via the mitochondrial Na+/Ca2+ exchanger strongly reduced nuclear import of NFAT. Furthermore, preventing Ca2+ mobilization via the mitochondrial Na+/Ca2+ exchanger diminished NFAT-mediated transcription. Collectively, these data implicate activity-induced Ca2+ uptake and prolonged release from mitochondria as a novel regulatory mechanism in neuronal excitation–transcription coupling.