Mitochondria Suppress Local Feedback Activation of Inositol 1,4,5-Trisphosphate Receptors by Ca2+

Hajnóczky, György; Hager, R; Thomas, Andrew P.

doi:10.1074/jbc.274.20.14157

Cited by 249 publications

(171 citation statements)

References 34 publications

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“…These data indicate that both the magnitude (in the basal and nuclear regions) and rate of Ca 2ϩ release (in all cellular regions) are markedly increased by inhibition of mitochondrial Ca 2ϩ uptake. These data are consistent with previous studies (21) suggesting that mitochondrial Ca 2ϩ uptake suppresses the local feedback activation of Ca 2ϩ release by buffering local [Ca 2ϩ ]. One might also predict, from these data, that mitochondrial Ca 2ϩ uptake shapes [Ca 2ϩ ] i signals in all regions of the cell consistent with a homogeneous distribution of mitochondria.…”

Section: Cch-and Insp 3 -Evoked Ca 2ϩ Signals Are Significantly Slowesupporting

confidence: 83%

Modulation of [Ca2+] Signaling Dynamics and Metabolism by Perinuclear Mitochondria in Mouse Parotid Acinar Cells

Bruce

Giovannucci²,

Blinder

et al. 2004

Journal of Biological Chemistry

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[Ca 2ϩ ] i signals may be tuned to evoke specific physiological responses in these cells. The major function of pancreatic acinar cells is the exocytosis of zymogen granules that can be activated by apically confined [Ca 2ϩ ] i signals (6), suggested to be the major physiological [Ca 2ϩ ] i signal evoked by threshold agonist concentrations (7). These apically confined [Ca 2ϩ ] i signals are in part because of the distribution of mitochondria, which form a belt around the apically located zymogen granules (8, 9). These perigranular mitochondria likely serve two main functions. First, mitochondrial Ca 2ϩ uptake provides a buffer barrier thereby preventing the spread of [Ca 2ϩ ] i waves to the basal part of the cell (8 -10). Second, the Ca 2ϩ taken up by mitochondria drives ATP production locally for the energy-consuming exocytotic process (11). The major function of parotid acinar cells is fluid secretion, and this is most effectively activated by rapid global [Ca 2ϩ ] i signals. We proposed that rapid global [Ca 2ϩ ] i signals facilitate the almost simultaneous activation of Ca 2ϩ -dependent Cl Ϫ channels on the apical membrane and Ca 2ϩ -dependent K ϩ channels on the basolateral membrane (5). The latter maintain the membrane potential at hyperpolarizing potentials and the driving force for Cl Ϫ efflux, thereby ensuring efficient ion and water movement (12). Interestingly, even at threshold stimulation parotid acinar cells exhibit rapid global [Ca 2ϩ ] i signals, and apically confined [Ca 2ϩ ] i signals were never observed (5). Given the many similarities between parotid and pancreatic acinar cells, the differences in the spatial and temporal patterns of [Ca 2ϩ ] i signaling between these two cell types 1 The abbreviations used are: [Ca 2ϩ ] i , intracellular calcium concentration; CCh, carbamylcholine (carbachol); FCCP, carbonyl cyanide 4-trifluoro-methoxyphenylhydrazone; OGB2, Oregon Green BAPTA 2; InsP 3 , inositol 1,4,5-trisphosphate; caged InsP 3 , D-myo-InsP 3 P-4(5)-1-(2-nitrophenyl)-ethyl ester; CaM, calmodulin; RuRed, ruthenium red; NPC, nuclear pore complex; rhod, rhodamine; TRITC, tetramethylrhodamine isothiocyanate.

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Section: Cch-and Insp 3 -Evoked Ca 2ϩ Signals Are Significantly Slowesupporting

confidence: 83%

Modulation of [Ca2+] Signaling Dynamics and Metabolism by Perinuclear Mitochondria in Mouse Parotid Acinar Cells

Bruce

Giovannucci²,

Blinder

et al. 2004

Journal of Biological Chemistry

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“…Receptor-mediated ER Ca 2ϩ release in astrocytes results in propagating waves traveling considerably faster when [Ca 2ϩ ] m uptake is blocked (Boitier et al, 1999). Also in hepatocytes, mitochondria are involved in setting the threshold for activation and defining the subcellular distribution of IP 3 -dependent Ca 2ϩ signaling (Hajnoczky et al, 1999). In addition the decrease of sPL-ER might result from a redistribution of these structures to regions more distal (Ͼ0.5 m) to the plasma membrane, a Ca 2ϩ -dependent mechanism previously observed in cultured cells (Subramanian and Meyer, 1997).…”

Section: Discussionmentioning

confidence: 99%

Deficiency in parvalbumin, but not in calbindin D-28k upregulates mitochondrial volume and decreases smooth endoplasmic reticulum surface selectively in a peripheral, subplasmalemmal region in the soma of Purkinje cells

et al. 2006

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Abstract-The Ca 2؉ -binding proteins parvalbumin (PV) and calbindin D-28k (CB) are key players in the intracellular Ca 2؉ -buffering in specific cells including neurons and have profound effectson spatiotemporal aspects of Ca 2؉ transients. The previously observed increase in mitochondrial volume density in fast-twitch muscle of PV؊/؊ mice is viewed as a specific compensation mechanism to maintain Ca 2؉ homeostasis. Since cerebellar Purkinje cells (PC) are characterized by high expression levels of the Ca 2؉ buffers PV and CB, the question was raised, whether homeostatic mechanisms are induced in PC lacking these buffers. Mitochondrial volume density, i.e. relative mitochondrial mass was increased by 40% in the soma of PV؊/؊ PC. Upregulation of mitochondrial volume density was not homogenous throughout the soma, but was selectively restricted to a peripheral region of 1.5 m width underneath the plasma membrane. Accompanied was a decreased surface of subplasmalemmal smooth endoplasmic reticulum (sPL-sER) in a shell of 0.5 m thickness underneath the plasma membrane. These alterations were specific for the absence of the "slow-onset" buffer PV, since in CB؊/؊ mice neither changes in peripheral mitochondria nor in sPL-sER were observed. This implicates that the morphological alterations are aimed to specifically substitute the function of the slow buffer PV. We propose a novel concept that homeostatic mechanisms of components involved in Ca 2؉ homeostasis do not always occur at the level of similar or closely related molecules. Rather the cell attempts to restore spatiotemporal aspects of Ca 2؉ signals prevailing in the undisturbed (wildtype) situation by subtly fine tuning existing components involved in the regulation of Ca 2؉ fluxes.Key words: calcium-binding, buffers, EF-hand, homeostasis, morphology.Ca 2ϩ ions are such ubiquitous second messengers that meaningful information must be contained in the subtle spatiotemporal aspects of Ca 2ϩ transients. A complex machinery of Ca 2ϩ entry and release systems, mobile and immobile Ca 2ϩ buffers, transient Ca 2ϩ -storage devices and Ca 2ϩ -extrusion systems governs the shape and spreading of intracellular Ca 2ϩ transients (Berridge et al., 2003). Affinities, kinetics of binding and release of Ca 2ϩ ions, the relative mobility and the geometrical distribution of all components, that is, the interplay between these systems finally shapes the spatiotemporal aspects of a Ca 2ϩ signal. Cerebellar Purkinje cells (PC) are characterized by extensive Ca 2ϩ signaling in somata, dendrites and spines elicited by either climbing fiber or parallel fiber stimulation. Following depolarization-evoked rises in the intracellular Ca 2ϩ concentration ([Ca 2ϩ ] i ) in the PC somata, endoplasmic reticulum (ER) and plasma membrane Ca 2ϩ pumps and the Na ϩ -Ca 2ϩ exchanger contribute to PC [Ca 2ϩ ] i clearance (Fierro et al., 1998). Since these systems only accounted for approximately 60% of total Ca 2ϩ clearing, mitochondria were additionally postulated to play a role. These organelles have...

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“…Consequent mitochondrial Ca 2ϩ uptake, via a yet unidentified Ca 2ϩ channel of the inner mitochondrial membrane (the mitochondrial Ca 2ϩ uniporter, MCU), regulates different processes: Aerobic metabolism (16), release of caspase cofactors (17), and feedback control of neighboring ER or plasma membrane Ca 2ϩ channels (18,19). The ER and mitochondria are thus crucial nodes at which intracellular Ca 2ϩ fluxes and functional outcomes are governed (20).…”

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confidence: 99%

Intramitochondrial calcium regulation by the FHIT gene product sensitizes to apoptosis

Rimessi

Marchi

Fotino

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Despite the growing interest in the Fhit tumor suppressor protein, frequently deleted in human cancers, the mechanism of its powerful proapoptotic activity has remained elusive. We here demonstrate that Fhit sensitizes the low-affinity Ca 2؉ transporters of mitochondria, enhancing Ca 2؉ uptake into the organelle both in intact and in permabilized cells, and potentiating the effect of apoptotic agents. This effect can be attributed to the fraction of Fhit sorted to mitochondria, as a fully mitochondrial Fhit (a chimeric protein including a mitochondrial targeting sequence) retains the Ca 2؉ signaling properties of Fhit and the proapoptotic activity of the native protein (whereas the effects on the cell cycle are lost). Thus, the partial sorting of Fhit to mitochondria allows to finely tune the sensitivity of the organelle to the highly pleiomorphic Ca 2؉ signals, synergizing with apoptotic challenges. This concept, and the identification of the molecular machinery, may provide ways to act on apoptotic cell death and its derangement in cancer.calcium signaling ͉ mitochondria ͉ oncosopressor ͉ oxidative stress T he fragile histidine triad (FHIT) gene, isolated by positional cloning, encompasses the most common human fragile site FRA3B at 3p14.2. This chromosomal region is involved in hemizygous and homozygous deletions, and indeed mutations of FHIT were demonstrated in a large variety of human tumors (1-4). FHIT encodes a 17-kDa protein (Fhit) that is abundantly expressed in normal human lung, stomach, kidney, and other epithelial tissues, whereas most tumors and tumor-derived cell lines do not express Fhit or show markedly reduced levels of the protein (5). Fhit knock-out mice are more susceptible to cancer development than their wild-type counterparts (6), and FHIT gene therapy can prevent and reverse tumors in carcinogen-exposed Fhit-deficient mice (7). However, the precise molecular mechanism involved in the antitumor function of FHIT remains largely unclear.Fhit is partly localized in mitochondria, and interaction with Hsp60/ Hsp10 could be important for correct refolding after import and Fhit stability (8). This compartmentalization of Fhit could reveal a transcription-independent regulation of cell fate. Indeed, mitochondria are at the crossroad of numerous apoptotic pathways that synergize in triggeringthemorphologicaltransitionsunderlyingthereleaseofproapoptotic factors into the cytoplasm (9-11). In most cases, Ca 2ϩ acts as a fundamental sensitizing factor, and anti-apoptotic proteins, such as Bcl-2, have been shown to reduce ER Ca 2ϩ levels, and agonistdependent release and mitochondrial loading (12)(13)(14).Different agents induce Ca 2ϩ release from the ER Ca 2ϩ store through the IP 3 R Ca 2ϩ release channel (15). Consequent mitochondrial Ca 2ϩ uptake, via a yet unidentified Ca 2ϩ channel of the inner mitochondrial membrane (the mitochondrial Ca 2ϩ uniporter, MCU), regulates different processes: Aerobic metabolism (16), release of caspase cofactors (17), and feedback control of neighboring ER or plasma ...

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Mitochondria Suppress Local Feedback Activation of Inositol 1,4,5-Trisphosphate Receptors by Ca2+

Cited by 249 publications

References 34 publications

Modulation of [Ca2+] Signaling Dynamics and Metabolism by Perinuclear Mitochondria in Mouse Parotid Acinar Cells

Modulation of [Ca2+] Signaling Dynamics and Metabolism by Perinuclear Mitochondria in Mouse Parotid Acinar Cells

Deficiency in parvalbumin, but not in calbindin D-28k upregulates mitochondrial volume and decreases smooth endoplasmic reticulum surface selectively in a peripheral, subplasmalemmal region in the soma of Purkinje cells

Intramitochondrial calcium regulation by the FHIT gene product sensitizes to apoptosis

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