Calcium - a life and death signal

Berridge, Michael J.; Bootman, Martin D.; Lipp, Peter

doi:10.1038/27094

Cited by 1,901 publications

(1,424 citation statements)

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“…Previous work showed that Ca 2+ homeostasis is dysregulated in cellular models of AD, as well as in human AD brains (Berridge, Bootman & Lipp, 1998; Celsi et al., 2009; Garwood et al., 2013). Surprisingly, our data showed decreased levels of free calcium, both in mitochondria and in cytoplasm, after the addition of the Aβ peptides.…”

Section: Discussionmentioning

confidence: 99%

Carbonic anhydrase inhibition selectively prevents amyloid β neurovascular mitochondrial toxicity

et al. 2018

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SummaryMounting evidence suggests that mitochondrial dysfunction plays a causal role in the etiology and progression of Alzheimer's disease (AD). We recently showed that the carbonic anhydrase inhibitor (CAI) methazolamide (MTZ) prevents amyloid β (Aβ)‐mediated onset of apoptosis in the mouse brain. In this study, we used MTZ and, for the first time, the analog CAI acetazolamide (ATZ) in neuronal and cerebral vascular cells challenged with Aβ, to clarify their protective effects and mitochondrial molecular mechanism of action. The CAIs selectively inhibited mitochondrial dysfunction pathways induced by Aβ, without affecting metabolic function. ATZ was effective at concentrations 10 times lower than MTZ. Both MTZ and ATZ prevented mitochondrial membrane depolarization and H2O2 generation, with no effects on intracellular pH or ATP production. Importantly, the drugs did not primarily affect calcium homeostasis. This work suggests a new role for carbonic anhydrases (CAs) in the Aβ‐induced mitochondrial toxicity associated with AD and cerebral amyloid angiopathy (CAA), and paves the way to AD clinical trials for CAIs, FDA‐approved drugs with a well‐known profile of brain delivery.

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Section: Discussionmentioning

confidence: 99%

Carbonic anhydrase inhibition selectively prevents amyloid β neurovascular mitochondrial toxicity

et al. 2018

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“…1 In isolated mitochondria, Immunoblot analysis using anti-VDAC, anti-GFP or anti-actin antibodies 68 h after transfection. Cells were washed with PBS, resuspended in a solution containing 1% Triton X-100 and protease inhibitors, sonicated and sample aliquots (50 mg of protein) were subjected to SDS-PAGE and immunostaining.…”

Section: Vdac Divalent Cation Binding Sitesmentioning

confidence: 99%

“…The release of apoptogenic intermediates such as cytochrome c from the intermembrane space appears to be a central event in the initiation of the cascade that leads to programmed cell death. [1][2][3][4] Mitochondrial Ca 2 þ overload also appears to induce both apoptotic and necrotic cell death. Mitochondria respond to an apoptotic signal by an alteration in the permeability of the mitochondrial membranes, termed permeability transition (PT), and this, in turn, may leads to apoptotic cell death.…”

Section: Introductionmentioning

confidence: 99%

“…Mitochondria respond to an apoptotic signal by an alteration in the permeability of the mitochondrial membranes, termed permeability transition (PT), and this, in turn, may leads to apoptotic cell death. [1][2][3][4] Two possible models have been proposed for this membrane permeability change. In the first model, an impairment of ATP/ADP antiport leads to hyperpolarization that promotes an osmotic matrix swelling.…”

Section: Introductionmentioning

confidence: 99%

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The voltage-dependent anion channel-1 modulates apoptotic cell death

et al. 2005

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The role of the voltage-dependent anion channel (VDAC) in cell death was investigated using the expression of native and mutated murine VDAC1 in U-937 cells and VDAC inhibitors. Glutamate 72 in VDAC1, shown previously to bind dicyclohexylcarbodiimide (DCCD), which inhibits hexokinase isoform I (HK-I) binding to mitochondria, was mutated to glutamine. Binding of HK-I to mitochondria expressing E72Q-mVDAC1, as compared to native VDAC1, was decreased by B70% and rendered insensitive to DCCD. HK-I and ruthenium red (RuR) reduced the VDAC1 conductance but not that of E72Q-mVDAC1. Overexpression of native or E72Q-mVDAC1 in U-937 cells induced apoptotic cell death (80%). RuR or overexpression of HK-I prevented this apoptosis in cells expressing native but not E72Q-mVDAC1. Thus, a single amino-acid mutation in VDAC prevented HK-I-or RuR-mediated protection against apoptosis, suggesting the direct VDAC regulation of the mitochondria-mediated apoptotic pathway and that the protective effects of RuR and HK-I rely on their binding to VDAC.

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“…Accumulated evidence suggests that AD is also linked to an imbalance of intracellular Ca 2+ homeostasis (Bezprozvanny & Mattson, 2008; Green & LaFerla, 2008; Marambaud et al ., 2009; Fernandez‐Morales et al ., 2012), because Ca 2+ plays a critical role in maintaining cell survival; for example, a mild elevation of [Ca 2+ ] c promotes neuronal survival and plasticity, whereas more pronounced elevations can cause neurotoxicity (Berridge et al ., 1998; Cano‐Abad et al ., 2001). Thus, alterations in Ca 2+ homeostatic mechanisms associated with aging, mutations in amyloid precursor protein (APP) and presenilins, and dysfunctional Ca 2+ fluxes at the endoplasmic reticulum (ER) can promote neuronal cell death (Bezprozvanny & Mattson, 2008).…”

Section: Introductionmentioning

confidence: 99%

CALHM1 and its polymorphism P86L differentially control Ca²⁺ homeostasis, mitogen‐activated protein kinase signaling, and cell vulnerability upon exposure to amyloid β

et al. 2015

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SummaryThe mutated form of the Ca2+ channel CALHM1 (Ca2+ homeostasis modulator 1), P86L‐CALHM1, has been correlated with early onset of Alzheimer's disease (AD). P86L‐CALHM1 increases production of amyloid beta (Aβ) upon extracellular Ca2+ removal and its subsequent addback. The aim of this study was to investigate the effect of the overexpression of CALHM1 and P86L‐CALHM, upon Aβ treatment, on the following: (i) the intracellular Ca2+ signal pathway; (ii) cell survival proteins ERK1/2 and Ca2+/cAMP response element binding (CREB); and (iii) cell vulnerability after treatment with Aβ. Using aequorins to measure the effect of nuclear Ca2+ concentrations ([Ca2+]n) and cytosolic Ca2+ concentrations ([Ca2+]c) on Ca2+ entry conditions, we observed that baseline [Ca2+]n was higher in CALHM1 and P86L‐CALHM1 cells than in control cells. Moreover, exposure to Aβ affected [Ca2+]c levels in HeLa cells overexpressing CALHM1 and P86L‐CALHM1 compared with control cells. Treatment with Aβ elicited a significant decrease in the cell survival proteins p‐ERK and p‐CREB, an increase in the activity of caspases 3 and 7, and more frequent cell death by inducing early apoptosis in P86L‐CALHM1‐overexpressing cells than in CALHM1 or control cells. These results suggest that in the presence of Aβ, P86L‐CALHM1 shifts the balance between neurodegeneration and neuronal survival toward the stimulation of pro‐cytotoxic pathways, thus potentially contributing to its deleterious effects in AD.

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Calcium - a life and death signal

Cited by 1,901 publications

References 23 publications

Carbonic anhydrase inhibition selectively prevents amyloid β neurovascular mitochondrial toxicity

Carbonic anhydrase inhibition selectively prevents amyloid β neurovascular mitochondrial toxicity

The voltage-dependent anion channel-1 modulates apoptotic cell death

CALHM1 and its polymorphism P86L differentially control Ca²⁺ homeostasis, mitogen‐activated protein kinase signaling, and cell vulnerability upon exposure to amyloid β

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Calcium - a life and death signal

Cited by 1,901 publications

References 23 publications

Carbonic anhydrase inhibition selectively prevents amyloid β neurovascular mitochondrial toxicity

Carbonic anhydrase inhibition selectively prevents amyloid β neurovascular mitochondrial toxicity

The voltage-dependent anion channel-1 modulates apoptotic cell death

CALHM1 and its polymorphism P86L differentially control Ca2+ homeostasis, mitogen‐activated protein kinase signaling, and cell vulnerability upon exposure to amyloid β

Contact Info

Product

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CALHM1 and its polymorphism P86L differentially control Ca²⁺ homeostasis, mitogen‐activated protein kinase signaling, and cell vulnerability upon exposure to amyloid β