Cytochrome c binds to inositol (1,4,5) trisphosphate receptors, amplifying calcium-dependent apoptosis

Boehning, Darren; Patterson, Randen L.; Sedaghat, Leela; Glebova, Natalia O.; Kurosaki, Tomohiro; Snyder, Solomon H.

doi:10.1038/ncb1063

Cited by 575 publications

(459 citation statements)

References 32 publications

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“…The organelle principally involved in the integration of such stressors, and of proapoptotic and antiapoptotic signals in general, is the mitochondrion, working in close liaison with the endoplasmic reticulum 11,12,39 . Mitochondria are the barometer of the cell, responding to the state of health or disease in all parts of the cell, from the nucleus to the cytoplasm, integrating the disparate stresses to repress or activate the apoptotic pathway.…”

Section: Mitochondrial Rons Influence Cell Deathmentioning

confidence: 99%

Lifespan and mitochondrial control of neurodegeneration

et al. 2004

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We examine the allometric (comparative scaling) relationships between rates of neurodegeneration resulting from equivalent mutations in a diverse group of genes from five mammalian species with different maximum lifespan potentials. In both retina and brain, rates of neurodegeneration vary by as much as two orders of magnitude and are strongly correlated with maximum lifespan potential and rates of formation of mitochondrial reactive oxygen and nitrogen species (RONS). Cell death in these disorders is directly or indirectly regulated by the intrinsic mitochondrial cell death pathway. Mitochondria are the main source of RONS production and integrate cellular stress signals to coordinate the intrinsic pathway. We propose that these two functions are intimately related and that steadystate RONS-mediated signaling or damage to the mitochondrial stress-integration machinery is the principal factor setting the probability of cell death in response to a diverse range of cellular stressors. This provides a new and unifying framework for investigating neurodegenerative disorders.Cell death in inherited neurodegenerative disorders most commonly occurs by apoptosis 1-4 . The evidence is often indirect and inferred on the basis of characteristic morphological changes, such as chromatin compaction and cell shrinkage, or evidence of caspase activation, but in many cases it is more reliably based on multiple lines of evidence [1][2][3][4] . Caspase-independent cell death also occurs, although the precise mechanisms are less well understood and evidence that this occurs in inherited neurodegenerations is sparse. In these disorders, cell death occurs with a probability that is constant through part or all of the adult lifespan, consistent with a steady-state (one-hit or exponential kinetics) rather than a cumulative damage model 5,6 . The retina is a particularly well understood model of neurodegeneration. Mutations in more than 100 genes are known to cause neurodegeneration of retinal photoreceptors (RetNet; see URL below); these affect virtually all areas of metabolism and all parts of the cell 7-9 .Two main pathways lead to the activation of cysteine proteases or caspases that execute the apoptotic death program [10][11][12] . The extrinsic pathway involves cell-surface signaling complexes (e.g., Fas or FasL), which trigger the cell death cascade by activating caspase 8 and downstream caspases. The intrinsic, or mitochondrial, pathway controls activation of caspase 9, through the adaptor molecule Apaf-1, by regulating release of cytochrome c from mitochondria. Proapoptotic and antiapoptotic members of the Bcl-2 family and various stress and survival signals regulate the release of cytochrome c. Proapoptotic signals can also release proteins such as Smac and Omi, which antagonize IAP (inhibitor of apoptosis) proteins to activate cell death caspases, from the mitochondrial intermembrane space.Evidence from animal models of human photoreceptor degeneration suggests that the mitochondrial, rather than the extrinsic, cell death pa...

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Section: Mitochondrial Rons Influence Cell Deathmentioning

confidence: 99%

Lifespan and mitochondrial control of neurodegeneration

et al. 2004

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“…For example, mutual interactions between cytochrome c and inositol 1,4,5 triphosphate receptor (InsP 3 R) have been reported that are believed to amplify the apoptotic signals. 20 InsP 3 R is an ER membrane protein responsible for promoting ER Ca 2 þ release into cytosol. It has been proposed that a feed-forward mechanism exists such that early in apoptosis cytochrome c and InsP 3 R interactions promote further releases of Ca 2 þ from the ER into cytosol and subsequent excessive release of cytochrome c from mitochondria, thereby further amplifying the apoptotic effects.…”

Section: Introductionmentioning

confidence: 99%

“…It has been proposed that a feed-forward mechanism exists such that early in apoptosis cytochrome c and InsP 3 R interactions promote further releases of Ca 2 þ from the ER into cytosol and subsequent excessive release of cytochrome c from mitochondria, thereby further amplifying the apoptotic effects. 20 PUMA is a newer member of the Bcl-2 family and, thus, very little is known about its role in apoptosis that is induced in response to alterations in intracellular Ca 2 þ homeostasis. TG is a sesqueterpene lactone that perturbs calcium (Ca 2 þ ) homeostasis by inhibiting the ER Ca 2 þ ATPases.…”

Section: Introductionmentioning

confidence: 99%

“…21 It is now well documented that perturbations in intracellular Ca 2 þ homeostasis due to alterations in the ER Ca 2 þ contents and Ca 2 þ movement between the ER and mitochondria profoundly affect cellular sensitivity to apoptotic stimuli. 15,20,22,23 In fact, excessive ER Ca 2 þ pool depletion mediated by TG is believed to induce 'ER stress' that triggers apoptosis.…”

Section: Introductionmentioning

confidence: 99%

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Transcriptional upregulation of PUMA modulates endoplasmic reticulum calcium pool depletion-induced apoptosis via Bax activation

Luo

Huang

et al. 2005

Cell Death Differ

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PUMA, a key mediator of p53-induced apoptosis, is a BH3-only domain proapoptotic protein that localizes to mitochondria and interacts with antiapoptotic Bcl-2 and Bcl-X L . Recent evidence implicates Bax to be an important mediator of PUMA-activated apoptotic signals. We have previously demonstrated that Bax deficiency significantly affects thapsigargin (TG)-mediated endoplasmic reticulum calcium pool depletion-induced apoptosis. We now present evidence that TG upregulates PUMA expression and that although Baxdeficient cells exhibit resistance to TG, Bax deficiency does not attenuate TG upregulation of PUMA expression. Furthermore, TG transcriptionally upregulates PUMA expression in a p53-independent manner and that PUMA-deficient cells are more resistant to undergo TG-induced apoptosis than the PUMA-proficient counterparts. Thus, our results demonstrate that TG engages PUMA and Bax for full transduction of apoptotic signals and both PUMA and Bax appear to exist in the same TG-activated apoptotic pathway in which PUMA may reside upstream of Bax.

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“…It is possible that these calcium events are coordinated with augmented cytochrome c release. 58 In this scenario, one can suggest that Ca 2 þ released in one cell that has high levels of Bax may serve to send Bax signals to other cells via Ca 2 þ release. Thus, in addition to its intracellular effects, Ca 2 þ would contribute to propagate signals related to perturbations in cytosolic or stored Ca 2 þ levels.…”

Section: Discussionmentioning

confidence: 99%

Bax affects intracellular Ca2+ stores and induces Ca2+ wave propagation

et al. 2004

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In the present study, we evaluated proapoptotic protein Bax on mitochondria and Ca 2 þ homeostasis in primary cultured astrocytes. We found that recombinant Bax (rBax, 10 and 100 ng/ml) induces a loss in mitochondrial membrane potential (DW m ). This effect might be related to the inhibition of respiratory rates and a partial release of cytochrome c, which may change mitochondrial morphology. The loss of DW m and a selective permeabilization of mitochondrial membranes contribute to the release of Ca 2 þ from the mitochondria. This was inhibited by cyclosporin A (5 lM) and Ruthenium Red (1 lg/ml), indicating the involvement of mitochondrial Ca 2 þ transport mechanisms. Bax-induced mitochondrial Ca 2 þ release evokes Ca 2 þ waves and wave propagation between cells. Our results show that Bax induces mitochondrial alteration that affects Ca 2 þ homeostasis and signaling. These changes show that Ca 2 þ signals might be correlated with the proapoptotic activities of Bax.

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Cytochrome c binds to inositol (1,4,5) trisphosphate receptors, amplifying calcium-dependent apoptosis

Cited by 575 publications

References 32 publications

Lifespan and mitochondrial control of neurodegeneration

Lifespan and mitochondrial control of neurodegeneration

Transcriptional upregulation of PUMA modulates endoplasmic reticulum calcium pool depletion-induced apoptosis via Bax activation

Bax affects intracellular Ca2+ stores and induces Ca2+ wave propagation

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