Mitochondria respond to and control intracellular calcium mobilization elicited by a wide range of hormones and growth factors. Evidence is emerging in support of the idea that propagation of the calcium signal to the mitochondria during short lasting Ca2+ release events is ensured by a local [Ca2+] regulation between IP3-activated endoplasmic reticulum Ca2+ release sites and mitochondrial Ca2+ uptake sites. However, the structure of the intimate ER-mitochondrial interaction and the functional organization of the local calcium coupling remain to be elucidated. Our principal hypothesis is that the local calcium signaling between ER and mitochondria is facilitated by a direct physical coupling between closely apposed regions of the ER and mitochondrial membranes. At these discrete junctions, IP3-dependent Ca2+ release sites are concentrated and activated in a coordinated manner during calcium spikes. Also, we propose that the mitochondrial Ca2+ uptake sites display changes in Ca2+ permeability that last for longer than the initial Ca2+ signal. This memory function that we call """"""""plasticity"""""""" may be particularly important in the decoding of repetitive calcium spikes by the mitochondria. Furthermore, we suggest that the amount of activated IP3R and the Ca2+ loading state of the ER are critical determinants of the fraction of released Ca2+ delivered to the mitochondria. In order to visualize the mitochondrial calcium signal down to the level of individual mitochondria and to dissect the mechanism underlying the ER-mitochondrial calcium coupling, we propose to use high spatial/temporal resolution fluorescence/confocaL'multiphoton imaging, including some novel approaches. We have established: 1. direct measurements of [Ca2+] in the stores of interest, 2. quantitative analysis of Ca2+ release and mitochondrial Ca2+ uptake and 3. a fluorometric assay to monitor the permeability of the mitochondrial Ca2+ uptake sites. Our studies were among the first to demonstrate the critical role of a local coupling in IP3R-driven mitochondrial Ca2+ signaling and have resulted in the preliminary data that allowed us to formulate the hypotheses listed above. Understanding the physiological control of mitochondrial Ca2+ uptake will not only afford insights into to control of mitochondrial functions (e.g., ATP production, feedback on cytosolic calcium signaling, initiation of apoptosis) but will also provide a key component in elucidating the mechanisms underlying mitochondrial diseases.
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