Mitochondrial Calcium Homeostasis: Mechanisms and Molecules

Vandecasteele, Grégoire; Szabadkai, György; Meneghesso, Gaudenzio

doi:10.1080/15216540152846028

Cited by 57 publications

(39 citation statements)

References 59 publications

(101 reference statements)

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“…Sustained Ca 2ϩ release from the ER can trigger Ca 2ϩ uptake by the mitochondria (26,36). The mitochondria possess an exceptional capacity to sequester Ca 2ϩ and buffer local variations in [Ca 2ϩ ] c levels via the activity of electrophoretic uniporters localized in the inner membrane (26,37). The close proximity of the mitochondria to the ER is believed to facilitate this process, which is possibly mediated via ER-mitochondria contact sites (37,38).…”

Section: Discussionmentioning

confidence: 99%

“…The mitochondria possess an exceptional capacity to sequester Ca 2ϩ and buffer local variations in [Ca 2ϩ ] c levels via the activity of electrophoretic uniporters localized in the inner membrane (26,37). The close proximity of the mitochondria to the ER is believed to facilitate this process, which is possibly mediated via ER-mitochondria contact sites (37,38). Mitochondrial Ca 2ϩ uptake has long been known to stimulate the turnover of matrix dehydrogenases coupled to the tricarboxylic acid cycle.…”

Section: Discussionmentioning

confidence: 99%

“…Mitochondrial Ca 2ϩ uptake has long been known to stimulate the turnover of matrix dehydrogenases coupled to the tricarboxylic acid cycle. This activity provides substrates for mitochondrial respiration, which can promote an increase in ⌬⌿ m (26,37,39,40).…”

Section: Discussionmentioning

confidence: 99%

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Evidence Supporting a Role for Calcium in Apoptosis Induction by the Synthetic Triterpenoid 2-Cyano-3,12-dioxooleana-1,9-dien-28-oic Acid (CDDO)

Hail

Konopleva

Sporn

et al. 2004

Journal of Biological Chemistry

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The synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO) is a novel anticancer agent that induces apoptosis in tumor cells. The cytotoxic stress underpinning CDDO-induced apoptosis has not been established. This study compared and contrasted the effects of CDDO on COLO 16 human skin cancer cells and their respiration-deficient ( 0 ) clones to elucidate the stress signal responsible for initiating apoptosis. CDDO promoted apoptosis in COLO 16 cells in a doseand time-dependent manner. The 0 clones appeared to be more sensitive to CDDO-induced apoptosis implying that the disruption of mitochondrial respiration was not directly associated with triggering cell death. After a 4-h exposure to CDDO, mitochondrial inner transmembrane potential-sensitive dyes revealed mitochondrial hyperpolarization in the COLO 16 cells and mitochondrial depolarization in the 0 clones. Electron microscopy illustrated that this exposure also promoted mitochondrial condensation, endoplasmic reticulum dilation, and chromatin condensation in the COLO 16 cells. Endoplasmic reticulum dilation and chromatin condensation were also observed in the 0 clones, but the mitochondria in these cells were markedly swollen implying that the disruption of intracellular Ca 2؉ homeostasis was associated with cell death. A Ca 2؉ -sensitive dye confirmed that CDDO increased cytoplasmic free Ca Triterpenoids derived from plants are used for medicinal purposes in many Asian countries and have been reported to have anticancer activity (1). Many of the plant-derived triterpenoids are considered weak anti-inflammatory and/or anticancer agents, which has encouraged the identification of novel synthetic analogues with greater potency (2). One such analogue, 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO), 1 has gained recognition as a promising cancer chemopreventive and therapeutic agent (3). In vitro studies have shown that nanomolar concentrations of CDDO can inhibit the proliferation of various human tumor cell types (3, 4), suppress the activity of inflammatory cytokines such as interferon-␥, interleukin-1, and tumor necrosis factor (2, 3), and inhibit the induction of inflammatory mediators such as cyclooxygenase-2 and nitric oxide synthase (2, 3). More recently, low micromolar concentrations (Յ10 M) of CDDO have been shown to induce apoptosis in human myeloid (5, 6) and lymphocytic leukemia cells (7), osteosarcoma cells (8), and breast cancer cells (4).Apoptosis is the mechanism utilized by metazoans to eliminate redundant or potentially deleterious cells and is considered an essential process for regulating tissue homeostasis. Apoptosis induction is arguably the most potent defense against cancer making it a desirable end point for both chemoprevention (9) and chemotherapy (10). Apoptosis is a relatively linear process. It is triggered by an initiation phase that is highly varied depending on cell type and the underlying stress stimulus (e.g. oxidative stress, DNA damage, ion fluctuations, and cytokines). This is followed by an effe...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Evidence Supporting a Role for Calcium in Apoptosis Induction by the Synthetic Triterpenoid 2-Cyano-3,12-dioxooleana-1,9-dien-28-oic Acid (CDDO)

Hail

Konopleva

Sporn

et al. 2004

Journal of Biological Chemistry

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“…Mitochondria play key roles in the maintenance of Ca 2+ ion homeostasis (Vandecasteele et al, 2001), and studies have shown that MF dynamics are important for the arrangement, distribution, and function of mitochondria (Vandecasteele et al, 2001). Mitochondria move along MFs and function as Ca 2+ stores in plant cells (Vandecasteele et al, 2001;Wang et al, 2004a), and stress induces mitochondrial-mediated cell death processes in plants (Yao et al, 2004;Lin et al, 2005;Gao et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

The Actin-Related Protein2/3 Complex Regulates Mitochondrial-Associated Calcium Signaling during Salt Stress inArabidopsis

et al. 2013

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Microfilament and Ca 2+ dynamics play important roles in stress signaling in plants. Through genetic screening of Arabidopsis thaliana mutants that are defective in stress-induced increases in cytosolic Ca 2+ ([Ca 2+ ] cyt ), we identified Actin-Related Protein2 (Arp2) as a regulator of [Ca 2+ ] cyt in response to salt stress. Plants lacking Arp2 or other proteins in the Arp2/3 complex exhibited enhanced salt-induced increases in [Ca 2+ ] cyt , decreased mitochondria movement, and hypersensitivity to salt. In addition, mitochondria aggregated, the mitochondrial permeability transition pore opened, and mitochondrial membrane potential Wm was impaired in the arp2 mutant, and these changes were associated with salt-induced cell death. When opening of the enhanced mitochondrial permeability transition pore was blocked or increases in [Ca 2+ ] cyt were prevented, the salt-sensitive phenotype of the arp2 mutant was partially rescued. These results indicate that the Arp2/3 complex regulates mitochondrial-dependent Ca 2+ signaling in response to salt stress.

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“…Following intracellular Ca 2+ elevation, mitochondria rapidly take up and accumulate Ca 2+ to maintain cellular Ca 2+ homeostasis (12). Studies also have shown that Ca 2+ uptake into mitochondria occurs through the mitochondrial Ca 2+ uniporter (12,13), and that mitochondrial Ca 2+ influx can increase ATP production by activating the TCA cycle, as well as enhance the activities of the electron transportchain enzymes and the ATP synthase complex (14)(15)(16)(17). Nevertheless, the relationship between mitochondrial energetic status and mitochondrial movement remains controversial.…”

mentioning

confidence: 99%

Mitochondrial matrix Ca ² ⁺ as an intrinsic signal regulating mitochondrial motility in axons

Chang

Niescier

Min

2011

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

134

111

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The proper distribution of mitochondria is particularly vital for neurons because of their polarized structure and high energy demand. Mitochondria in axons constantly move in response to physiological needs, but signals that regulate mitochondrial movement are not well understood. Aside from producing ATP, Ca 2+ buffering is another main function of mitochondria. Activities of many enzymes in mitochondria are also Ca 2+ -dependent, suggesting that intramitochondrial Ca 2+ concentration is important for mitochondrial functions. Here, we report that mitochondrial motility in axons is actively regulated by mitochondrial matrix Ca 2+ . Ca 2+ entry through the mitochondrial Ca 2+ uniporter modulates mitochondrial transport, and mitochondrial Ca 2+ content correlates inversely with the speed of mitochondrial movement. Furthermore, the miro1 protein plays a role in Ca 2+ uptake into the mitochondria, which subsequently affects mitochondrial movement.M itochondria are dynamic organelles that constantly move within cells and undergo morphological changes in response to physiological needs (1-3). In neurons, mitochondria are abundantly present throughout different subcellular compartments. The machineries and signals that transport mitochondria from the cell body (where they are synthesized) to the terminal need to be carefully regulated because of the highly polarized structure and lengthy axon of a neuron (4-6). Defects in transport of mitochondria can cause deleterious effects on mitochondrial functions in different parts of neurons, and hence affect neuronal survival and function (2, 3). Recent efforts to investigate mitochondrial transportation have provided significant new information regarding mitochondrial mobility, especially the mechanical components that modulate mitochondrial transport; however, it remains unclear whether intrinsic signals inside of mitochondria also actively regulate mitochondrial movement.Mitochondrial transport is mediated by interactions of the mitochondrial adaptor proteins to the kinesin and dynein motors, as well as binding of the motor proteins to the cytoskeleton track (7,8). It was posited that cytoplasmic Ca 2+ level is a key regulator of mitochondrial trafficking in axons and dendrites, and that intracellular Ca 2+ influx impedes mitochondrial movement by affecting the overall interactions between the mitochondrial adaptor, motor, and cytoskeleton track (9, 10). Two different mechanisms for Ca 2+ -mediated stop in mitochondrial trafficking were proposed. Wang and Schwarz suggested that Ca 2+ binding to the EF hand motif of the mitochondrial adaptor protein miro1 recruits kinesin-1 motor and, hence, derails kinesin-1 from the microtubule track, thereby stopping mitochondrial transportation in axons (10). Macaskill et al. proposed that following Ca 2+ influx induced by glutamate or neuronal activity, Ca 2+ binding to the EF hand motif of the miro1 protein causes miro1 to dissociate from the kinesin-1 motor, and hence halts mitochondrial movement (11). Although the mechanisms propose...

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Mitochondrial Calcium Homeostasis: Mechanisms and Molecules

Cited by 57 publications

References 59 publications

Evidence Supporting a Role for Calcium in Apoptosis Induction by the Synthetic Triterpenoid 2-Cyano-3,12-dioxooleana-1,9-dien-28-oic Acid (CDDO)

Evidence Supporting a Role for Calcium in Apoptosis Induction by the Synthetic Triterpenoid 2-Cyano-3,12-dioxooleana-1,9-dien-28-oic Acid (CDDO)

The Actin-Related Protein2/3 Complex Regulates Mitochondrial-Associated Calcium Signaling during Salt Stress inArabidopsis

Mitochondrial matrix Ca ² ⁺ as an intrinsic signal regulating mitochondrial motility in axons

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Mitochondrial Calcium Homeostasis: Mechanisms and Molecules

Cited by 57 publications

References 59 publications

Evidence Supporting a Role for Calcium in Apoptosis Induction by the Synthetic Triterpenoid 2-Cyano-3,12-dioxooleana-1,9-dien-28-oic Acid (CDDO)

Evidence Supporting a Role for Calcium in Apoptosis Induction by the Synthetic Triterpenoid 2-Cyano-3,12-dioxooleana-1,9-dien-28-oic Acid (CDDO)

The Actin-Related Protein2/3 Complex Regulates Mitochondrial-Associated Calcium Signaling during Salt Stress inArabidopsis

Mitochondrial matrix Ca 2 + as an intrinsic signal regulating mitochondrial motility in axons

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Product

Resources

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Mitochondrial matrix Ca ² ⁺ as an intrinsic signal regulating mitochondrial motility in axons