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(19) MITOCHONDRIAL Ca2+ SIGNALING IN LIFE AND DEATH G. Hajnóczky, G. Csordás,
M. Madesh and P. Pacher
Growing evidence suggests that propagation of cytosolic [Ca2+] ([Ca2+]c) oscillations to the mitochondria is important for the control of fundamental cellular functions such as ATP production and apoptosis. Delivery of [Ca2+]c spikes to the mitochondria is ensured by a local calcium signal transmission from sarco-endoplasmic reticulum (SR/ER) Ca2+ release channels to the neighboring mitochondrial Ca2+ uptake sites. A major goal of our studies is to delineate the mechanisms underlying local calcium signaling between SR/ER and mitochondria. To study generation of the fundamental elements of the mitochondrial [Ca2+] signal we used high temporal resolution imaging approaches and visualized propagation of elementary Ca2+ release events to the mitochondria. We have also developed new fluorescence approaches to monitor the permeability properties of the mitochondrial Ca2+ uptake sites. Using these methods we demonstrated that mitochondrial Ca2+ uptake sites display facilitation during Ca2+ release from SR/ER utilizing a feedback effect of Ca2+ taken up by mitochondria. This effect may be particularly important in optimizing delivery of Ca2+ to the mitochondria during repetitive [Ca2+]c oscillations. Other studies are to address the role of mitochondrial calcium signals in activation of the apoptotic machinery. Recently, we showed that IP3-mediated [Ca2+] spikes are an efficient and selective activator of the mitochondrial phase of the apoptotic machinery in cells exposed to stress factors such as ceramide, staurosporin. Our new studies demonstrated that ceramide causes dephosphorylation and translocation of Bad to the mitochondria and these effects are important for activation of the apoptotic machinery by mitochondrial [Ca2+] spiking. We have also investigated the subcellular spatial organization of calcium signal-driven apoptosis and report that mitochondria can ensure propagation of the apoptotic signal throughout the cell utilizing a local intermitochondrial communication. This novel mechanism involves that mitochondria release activators of the cytosolic components of the apoptotic cascade as well as factors that act on neighboring mitochondria to trigger further release events. The lateral signaling between mitochondria results in a regenerative process that is shown to propagate the apoptotic signal over several hundred micrometer distances at full strength.
For further information contact...Carmen Mannella: carmen@wadsworth.org |
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