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

Carvalho, A. C. P.; Sharpe, Juanita C.; Rosenstock, Tatiana R.; Teles, A F V; Kowaltowski, Alicia J.; Youle, Richard J.; Smaili, Soraya Soubhi

doi:10.1038/sj.cdd.4401508

Cited by 43 publications

(35 citation statements)

References 62 publications

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“…Oligomer Bax can evoke even mitochondrial permeability transition and mitochondrial swelling (25,47). Despite the accompanying release of proapoptotic mitochondrial proteins, mPT induced by oligomer Bax can lead to cyclophilin D-sensitive necrotic cell death (25,47). Besides tBid and Bax, Bak was reported to bind to VDAC and facilitate necrotic and apoptotic cell death (47)(48)(49)(50)(51).…”

Section: Discussionmentioning

confidence: 99%

“…Despite the accompanying release of proapoptotic mitochondrial proteins, mPT induced by oligomer Bax can lead to cyclophilin D-sensitive necrotic cell death (25,47). Besides tBid and Bax, Bak was reported to bind to VDAC and facilitate necrotic and apoptotic cell death (47)(48)(49)(50)(51). It is very likely that SOUL as a BH3 domain-only protein exerts its effect in a similar manner.…”

Section: Discussionmentioning

confidence: 99%

“…It is also known that Bax and Bak can oligomerize (53), and their oligomer forms are very effective in inducing cell death (25,47). Therefore, it is likely that oligomerization plays a role in the effect of SOUL.…”

Section: Discussionmentioning

confidence: 99%

“…Both are capable of permeabilizing the inner together with the outer mitochondrial membrane, inducing the release of proapoptotic mitochondrial proteins and promoting cell death. However, Bax can induce both necrotic and apoptotic cell death by itself (25,47,54), whereas SOUL can only facilitate cell death induced by other stimuli and direct it toward a necrotic mechanism, presumably by amplifying mitochondrial impairment.…”

Section: Discussionmentioning

confidence: 99%

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Facilitation of Mitochondrial Outer and Inner Membrane Permeabilization and Cell Death in Oxidative Stress by a Novel Bcl-2 Homology 3 Domain Protein

Szigeti

Hocsák

Rapolti

et al. 2010

Journal of Biological Chemistry

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We identified a sequence homologous to the Bcl-2 homology 3 (BH3) domain of Bcl-2 proteins in SOUL. Tissues expressed the protein to different extents. It was predominantly located in the cytoplasm, although a fraction of SOUL was associated with the mitochondria that increased upon oxidative stress. Recombinant SOUL protein facilitated mitochondrial permeability transition and collapse of mitochondrial membrane potential (MMP) and facilitated the release of proapoptotic mitochondrial intermembrane proteins (PMIP) at low calcium and phosphate concentrations in a cyclosporine A-dependent manner in vitro in isolated mitochondria. Suppression of endogenous SOUL by diced small interfering RNA in HeLa cells increased their viability in oxidative stress. Overexpression of SOUL in NIH3T3 cells promoted hydrogen peroxide-induced cell death and stimulated the release of PMIP but did not enhance caspase-3 activation. Despite the release of PMIP, SOUL facilitated predominantly necrotic cell death, as revealed by annexin V and propidium iodide staining. This necrotic death could be the result of SOUL-facilitated collapse of MMP demonstrated by JC-1 fluorescence. Deletion of the putative BH3 domain sequence prevented all of these effects of SOUL. Suppression of cyclophilin D prevented these effects too, indicating that SOUL facilitated mitochondrial permeability transition in vivo. Overexpression of Bcl-2 and Bcl-x L , which can counteract the mitochondriapermeabilizing effect of BH3 domain proteins, also prevented SOUL-facilitated collapse of MMP and cell death. These data indicate that SOUL can be a novel member of the BH3 domain-only proteins that cannot induce cell death alone but can facilitate both outer and inner mitochondrial membrane permeabilization and predominantly necrotic cell death in oxidative stress.We have previously observed that heme-binding protein 2/SOUL facilitates mitochondrial permeability transition and cell death without affecting reactive oxygen production (1). A data base search indicated that heme-binding protein 2/SOUL has a BH3 2 domain-like structure. BH3 domain-only proteins play a significant role in the processes of cell death and survival (2, 3). Mammalian cells express a group of evolutionarily conserved proteins known as the Bcl-2 (B-cell-associated leukemia protein 2) family. The effect of Bcl-2 proteins on the apoptotic process is due to the presence of one or more conserved regions of amino acid sequences, known as Bcl-2 homology (BH) domains. Based on their function, Bcl-2 proteins can have either proapoptotic (Bax, Bad, Bak, Bim, and Bid) or antiapoptotic (Bcl-2 and Bcl-x L ) properties. All antiapoptotic Bcl-2-related proteins described to date contain BH1, BH2, and sometimes BH4 domains in addition to the BH3 domain (4 -6). Proapoptotic family members either share the multidomain structure (e.g. Bax and Bak) or contain only the BH3 domain (e.g. Bim and Bid). Bcl-2 proteins containing only the BH3 domain have been suggested to play an important role in initiating mitochondrial-med...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Facilitation of Mitochondrial Outer and Inner Membrane Permeabilization and Cell Death in Oxidative Stress by a Novel Bcl-2 Homology 3 Domain Protein

Szigeti

Hocsák

Rapolti

et al. 2010

Journal of Biological Chemistry

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“…Microinjection and Ca 2ϩ Measurements-Astrocytes were loaded with 3 M Fura-2AM (Molecular Probes, Eugene, OR) for 30 min in microscopy buffer and then washed with intracellular buffer used previously (30). Fura-2 fluorescence microscopy and microinjection were conducted as described (30).…”

Section: Methodsmentioning

confidence: 99%

Nicotinic Acid Adenine Dinucleotide Phosphate (NAADP) Regulates Autophagy in Cultured Astrocytes

Pereira

Hirata

Fimia

et al. 2011

Journal of Biological Chemistry

116

111

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Nicotinic acid adenine dinucleotide phosphate (NAADP) is a potent Ca2؉ -mobilizing messenger that in many cells releases Ca 2؉ from the endolysosomal system. Recent studies have shown that NAADP-induced Ca 2؉ mobilization is mediated by the two-pore channels (TPCs). Whether NAADP acts as a messenger in astrocytes is unclear, and downstream functional consequences have yet to be defined. Here, we show that intracellular delivery of NAADP evokes Ca 2؉ signals from acidic organelles in rat astrocytes and that these signals are potentiated upon overexpression of TPCs. We also show that NAADP increases acidic vesicular organelle formation and levels of the autophagic markers, LC3II and beclin-1. NAADP-mediated increases in LC3II levels were reduced in cells expressing a dominant-negative TPC2 construct. Our data provide evidence that NAADP-evoked Ca 2؉ signals mediated by TPCs regulate autophagy. Increases in cytosolic Ca2ϩ regulate a myriad of cellular functions including information processing in the central nervous system (1). In many cells, these increases can be driven by mobilization of intracellular Ca 2ϩ stores (2). Much attention has focused on the endoplasmic reticulum as a Ca 2ϩ store (3), but accumulating evidence also implicates acidic organelles such as lysosomes in the control of Ca 2ϩ dynamics (4). In particular, NAADP 2 has emerged as a novel intracellular Ca 2ϩ -mobilizing messenger that links cell surface stimulation to the release of Ca 2ϩ from acidic Ca 2ϩ stores (5). Changes in the concentration of cytosolic Ca 2ϩ in glial cells are key for bidirectional control of neuronal activity (1). Previous studies have shown that extracellular application of NAADP can evoke Ca 2ϩ signals in astrocytes, consistent with a messenger role for NAADP in this cell type, following its internalization (6). Interpretation of these results, however, is clouded by the demonstrated lack of specificity with respect to related nucleotides (6) and by the potential activation by NAADP of cell surface purinergic receptors (7). Whether NAADP acts as an intracellular messenger in astrocytes is therefore unclear.Although the role of inositol trisphosphate and ryanodine receptors is established in mediating Ca 2ϩ release from the ER in response to inositol trisphosphate and cyclic ADP-ribose, respectively (2), the molecular basis for Ca 2ϩ release by NAADP from acidic organelles is less certain (8). In a series of recent studies, however, a novel family of Ca 2ϩ channels, known as the two-pore channels (TPCs), have emerged as likely targets (9). Thus, TPCs localize to endosomes and/or lysosomes through an identified targeting motif and enhance NAADPmediated cytosolic Ca 2ϩ signals when overexpressed (10 -12). Inhibition of TPC expression/function using siRNA (10), TPC knock-out mice (11), or a dominant-negative TPC construct (10) reduces NAADP-evoked Ca 2ϩ signals, and biophysical analyses indicate that TPCs are NAADP-gated Ca 2ϩ -permeable channels (13). Moreover, a functional role for TPCs has been identified in events such ...

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Overexpression of α‐synuclein in an astrocyte cell line promotes autophagy inhibition and apoptosis

Erustes

Stefani

Terashima

et al. 2017

J of Neuroscience Research

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α-Synuclein is the major component of neuronal cytoplasmic aggregates called Lewy bodies, the main pathological hallmark of Parkinson disease. Although neurons are the predominant cells expressing α-synuclein in the brain, recent studies have demonstrated that primary astrocytes in culture also express α-synuclein and regulate α-synuclein trafficking. Astrocytes have a neuroprotective role in several detrimental brain conditions; we therefore analyzed the effects of the overexpression of wild-type α-synuclein and its A30P and A53T mutants on autophagy and apoptosis. We observed that in immortalized astrocyte cell lines, overexpression of α-synuclein proteins promotes the decrease of LC3-II and the increase of p62 protein levels, suggesting the inhibition of autophagy. When these cells were treated with rotenone, there was a loss of mitochondrial membrane potential, especially in cells expressing mutant α-synuclein. The level of this decrease was related to the toxicity of the mutants because they show a more intense and sustained effect. The decrease in autophagy and the mitochondrial changes in conjunction with parkin expression levels may sensitize astrocytes to apoptosis.

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

Cited by 43 publications

References 62 publications

Facilitation of Mitochondrial Outer and Inner Membrane Permeabilization and Cell Death in Oxidative Stress by a Novel Bcl-2 Homology 3 Domain Protein

Facilitation of Mitochondrial Outer and Inner Membrane Permeabilization and Cell Death in Oxidative Stress by a Novel Bcl-2 Homology 3 Domain Protein

Nicotinic Acid Adenine Dinucleotide Phosphate (NAADP) Regulates Autophagy in Cultured Astrocytes

Overexpression of α‐synuclein in an astrocyte cell line promotes autophagy inhibition and apoptosis

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