Modulation of Mitochondrial Ca2+ Homeostasis by Bcl-2

Zhu, Liping; Ling, S. H.; Yu, Xiao Dan; Venkatesh, Leelavathi; Subramanian, T.; Chinnadurai, G.; Kuo, Tuan H.

doi:10.1074/jbc.274.47.33267

Cited by 107 publications

(68 citation statements)

References 47 publications

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“…The expression of Bcl-2-related proteins has been reported to affect intracellular Ca 2ϩ homeostasis (17,(25)(26)(27)(28)(29)(30)(31), although the molecular basis of these effects has remained unclear. The compensatory reduction in IP 3 R expression in response to increase in expression of an anti-apoptotic Bcl-2 protein reported here may account for many of the effects previously noted.…”

Section: Discussionmentioning

confidence: 99%

Bcl-X_Laffects Ca²⁺homeostasis by altering expression of inositol 1,4,5-trisphosphate receptors

Fox

Master

et al. 2002

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

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P roteins of the Bcl-2 family play critical roles in the regulation of programmed cell death (1-3). In response to stimuli such as growth factor withdrawal, loss of cellular attachment, or DNA damage, cells from multicellular organisms can initiate their own death through apoptosis. Under such conditions, the expression of anti-apoptotic Bcl-2 family members, including Bcl-2 and Bcl-X L, can prevent the initiation of an apoptotic response and maintain the survival and͞or promote the recovery of the cell. In contrast, overexpression of pro-apoptotic family members such as Bax and Bak promotes the initiation of apoptosis in response to cytotoxic insults. These results have demonstrated that Bcl-2 proteins function to regulate the apoptotic response. However, it is less clear whether Bcl-2 proteins play roles in regulating cellular physiology under non-apoptotic conditions.Bcl-2 and Bcl-X L are constitutively expressed and are localized to the endoplasmic reticulum (ER), perinuclear, and outer mitochondrial membranes. On the basis of their localization, Bcl-2 and Bcl-X L have been hypothesized to regulate mitochondrial physiology and͞or Ca 2ϩ metabolism (4, 5). Alternatively, these anti-apoptotic proteins may function primarily to oppose the pro-apoptotic functions of two other family members required for the initiation of programmed cell death, Bax and Bak (1-3). Both Bax and Bak exist in an inactive conformation in healthy cells, and they undergo conformational changes in response to apoptotic stimuli (6-8). These conformational changes then enable their participation in events that result in apoptosis.To address whether the anti-apoptotic protein Bcl-X L influences cellular physiology in the absence of apoptotic stimuli, we have carried out an oligonucleotide-based microarray analysis of 9,500 murine genes and expressed sequence tags (ESTs) to identify global changes in gene expression in response to Bcl-X L expression. Highly reproducible changes in the expression of several genes involved in the metabolism of calcium and other divalent cations were identified. The most dramatic change was observed for the type 1 inositol 1,4,5-trisphosphate (IP 3 ) receptor (IP 3 R), an intracellular Ca 2ϩ channel gated by the secondary messenger IP 3 . IP 3 R is responsible for the mobilization of Ca 2ϩ from intracellular stores in response to signals from receptors on the plasma membrane (9, 10). One response to the release of Ca 2ϩ through IP 3 R is enhanced coupling of mitochondrial oxidative phosphorylation rate to increased cellular demand as a consequence of activation of a signal transduction cascade (5, 11). We observed a dose-dependent reduction of IP 3 R protein in cells that overexpress Bcl-X L , which further correlated with a reduction in receptor-induced Ca 2ϩ flux and with a reduced ability to release Ca 2ϩ upon IP 3 treatment of ER vesicles. Also, reduction of mitochondrial membrane potential increased the binding of the transcription factor NFATc2 to the IP 3 R promoter and IP 3 R expression. This effect was ...

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Section: Discussionmentioning

confidence: 99%

Bcl-X_Laffects Ca²⁺homeostasis by altering expression of inositol 1,4,5-trisphosphate receptors

Fox

Master

et al. 2002

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

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“…Consistent with previous reports in other cell types (Dispersyn et al ., 1999;Ichas et al ., 1997;Armstrong et al ., 2001), we observed that FCCP decreased mitochondrial membrane potential and increased intracellular Ca 2+ in mouse embryos. FCCP and other protonophores increase intracellular Ca 2+ by release from mitochondria, which reflects compromised mitochondrial function (Babcock et al ., 1997;Zhu et al , 1999;Montero et al ., 2001). Furthermore, we found that FCCP-induced mitochondrial dysfunction is followed by increased ROS production.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial dysfunction leads to telomere attrition and genomic instability

et al. 2002

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SummaryMitochondrial dysfunction and oxidative stress have been implicated in cellular senescence, apoptosis, aging and aging-associated pathologies. Telomere shortening and genomic instability have also been associated with replicative senescence, aging and cancer. Here we show that mitochondrial dysfunction leads to telomere attrition, telomere loss, and chromosome fusion and breakage, accompanied by apoptosis. An antioxidant prevented telomere loss and genomic instability in cells with dysfunctional mitochondria, suggesting that reactive oxygen species are mediators linking mitochondrial dysfunction and genomic instability. Further, nuclear transfer protected genomes from telomere dysfunction and promoted cell survival by reconstitution with functional mitochondria. This work links mitochondrial dysfunction and genomic instability and may provide new therapeutic strategies to combat certain mitochondrial and aging-associated pathologies.

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“…Finally, Tsien and coworkers not only confirmed that Bcl-2 overexpression leads to decreased ER Ca 2 þ levels, but also showed that the green tea compound epigallocatechin gallate, known to bind and inactivate Bcl-2, restored [Ca 2 þ ] of the ER to that of normal cells. 47 We are aware that not all experts in the field concur with these conclusions -see, for example, Chen et al, 48 He et al, 49 Lam et al, 50 Wang et al, 51,52 Zhong et al, 53 Ichimiya et al, 54 Wei et al, 55 Kuo et al, 56 Zhu et al 57 But it is our biased opinion that in many of these studies the different conclusions depend on the specific experimental approach (indirect methods of monitoring Ca 2 þ in the ER, use of clones, etc.). A very interesting possibility would be that the modulation of Ca 2 þ handling by pro-and anti-apoptotic proteins is exerted because they can alter the gating properties of specific isoform of the IP 3 receptor, IP 3 R. If this is the case the effects of the pro-and anti-apoptotic proteins on Ca 2 þ handling should depend on the specific cell model employed and the expression profile of IP 3 Rs.…”

Section: Mitochondrial Ca 2 þ Homeostasis and Cell Death By Necrosis mentioning

confidence: 99%

Mitochondrial Ca2+ as a key regulator of cell life and death

et al. 2007

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Modulation of Mitochondrial Ca2+ Homeostasis by Bcl-2

Cited by 107 publications

References 47 publications

Bcl-X_Laffects Ca²⁺homeostasis by altering expression of inositol 1,4,5-trisphosphate receptors

Bcl-X_Laffects Ca²⁺homeostasis by altering expression of inositol 1,4,5-trisphosphate receptors

Mitochondrial dysfunction leads to telomere attrition and genomic instability

Mitochondrial Ca2+ as a key regulator of cell life and death

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Modulation of Mitochondrial Ca2+ Homeostasis by Bcl-2

Cited by 107 publications

References 47 publications

Bcl-XLaffects Ca2+homeostasis by altering expression of inositol 1,4,5-trisphosphate receptors

Bcl-XLaffects Ca2+homeostasis by altering expression of inositol 1,4,5-trisphosphate receptors

Mitochondrial dysfunction leads to telomere attrition and genomic instability

Mitochondrial Ca2+ as a key regulator of cell life and death

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Product

Resources

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Bcl-X_Laffects Ca²⁺homeostasis by altering expression of inositol 1,4,5-trisphosphate receptors

Bcl-X_Laffects Ca²⁺homeostasis by altering expression of inositol 1,4,5-trisphosphate receptors