NCLX is an essential component of mitochondrial Na
            <sup>+</sup>
            /Ca
            <sup>2+</sup>
            exchange

Palty, Raz; Silverman, William F.; Hershfinkel, Michal; Caporale, Teresa; Sensi, Stefano L.; Parnis, Julia; Nolte, Christiané; Fishman, Daniel; Shoshan‐Barmatz, Varda; Herrmann, Sharon; Khananshvili, Daniel; Sekler, Israel

doi:10.1073/pnas.0908099107

Cited by 702 publications

(609 citation statements)

References 36 publications

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“…Uptake into mitochondria leads to a clipping of Ca 2+ transients when they start to exceed a critical level of cytosolic Ca 2+ . A main mitochondrial Ca 2+ extrusion mechanism is likely mediated by a Na + /Ca 2+ exchanger (14).…”

Section: Resultsmentioning

confidence: 99%

Parallel adaptive feedback enhances reliability of the Ca ²⁺ signaling system

Abell

Ahrends

Bandara

et al. 2011

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

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Despite large cell-to-cell variations in the concentrations of individual signaling proteins, cells transmit signals correctly. This phenomenon raises the question of what signaling systems do to prevent a predicted high failure rate. Here we combine quantitative modeling, RNA interference, and targeted selective reaction monitoring (SRM) mass spectrometry, and we show for the ubiquitous and fundamental calcium signaling system that cells monitor cytosolic and endoplasmic reticulum (ER) Ca 2+ levels and adjust in parallel the concentrations of the store-operated Ca 2+ influx mediator stromal interaction molecule (STIM), the plasma membrane Ca 2+ pump plasma membrane Ca-ATPase (PMCA), and the ER Ca 2+ pump sarco/ER Ca 2+ -ATPase (SERCA). Model calculations show that this combined parallel regulation in protein expression levels effectively stabilizes basal cytosolic and ER Ca 2+ levels and preserves receptor signaling. Our results demonstrate that, rather than directly controlling the relative level of signaling proteins in a forward regulation strategy, cells prevent transmission failure by sensing the state of the signaling pathway and using multiple parallel adaptive feedbacks.absolute quantification of calcium signaling proteins | targeted proteomics | compensation mechanisms in signal transduction networks | cell signaling | protein abundance profiling R ecent studies in mammalian cells and lower eukaryotes showed a significant variation in the expression level of individual proteins between genetically identical cells (1, 2). These variations-often exceeding a factor of 2-likely reflect noise in transcription, mRNA turnover, translation, and protein degradation. This cell-to-cell variability creates a fundamental problem for signal transduction because even small differences in the relative levels of signaling components along a pathway lead to a processive degradation of signal transmission and failed physiological responses. However, cells typically manage to transmit signals correctly, overcoming protein expression variations by unknown mechanisms.Ca 2+ signals regulate fundamental eukaryotic processes that range from secretion, muscle contraction, and memory formation to activation and differentiation of immune cells (3, 4). Our detailed knowledge of the Ca 2+ signaling system makes this pathway ideally suited to address the puzzling question of how signal transmission processes can tolerate large variations in the expression level of the underlying signaling components. We hypothesized that additional control principles must exist to explain how the otherwise well-understood Ca 2+ signaling system avoids failure and copes with large cell-to-cell variations in protein expression. To keep cells in a signaling-competent state, the Ca 2+ signaling system employs a system of pumps and channels to tightly balance Ca 2+ fluxes across the endoplasmic reticulum (ER) and plasma membrane (PM). The highly coordinated regulation of calcium homeostasis raises the questions of whether the pumps and channels are alway...

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Section: Resultsmentioning

confidence: 99%

Parallel adaptive feedback enhances reliability of the Ca ²⁺ signaling system

Abell

Ahrends

Bandara

et al. 2011

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

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“…2010), a function performed by a CCX‐type Na + /Ca 2+ exchanger in animals (Palty et al . 2010), but by a less clear mechanism in plants (Wagner et al . 2016).…”

Section: Non‐plant Caxs – Lessons To Be Learned?mentioning

confidence: 99%

CAX‐ing a wide net: Cation/H⁺ transporters in metal remediation and abiotic stress signalling

2016

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Cation/proton exchangers (CAXs) are a class of secondary energised ion transporter that are being implicated in an increasing range of cellular and physiological functions. CAXs are primarily Ca2+ efflux transporters that mediate the sequestration of Ca2+ from the cytosol, usually into the vacuole. Some CAX isoforms have broad substrate specificity, providing the ability to transport trace metal ions such as Mn2+ and Cd2+, as well as Ca2+. In recent years, genomic analyses have begun to uncover the expansion of CAXs within the green lineage and their presence within non‐plant species. Although there appears to be significant conservation in tertiary structure of CAX proteins, there is diversity in function of CAXs between species and individual isoforms. For example, in halophytic plants, CAXs have been recruited to play a role in salt tolerance, while in metal hyperaccumulator plants CAXs are implicated in cadmium transport and tolerance. CAX proteins are involved in various abiotic stress response pathways, in some cases as a modulator of cytosolic Ca2+ signalling, but in some situations there is evidence of CAXs acting as a pH regulator. The metal transport and abiotic stress tolerance functions of CAXs make them attractive targets for biotechnology, whether to provide mineral nutrient biofortification or toxic metal bioremediation. The study of non‐plant CAXs may also provide insight into both conserved and novel transport mechanisms and functions.

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“…Ca 2ϩ accumulation by MCU is counteracted predominantly by mNCX (63). This exchanger, first described by Carafoli and co-workers (64), was recently identified by Sekler and co-workers (65), who demonstrated that silencing of NCLX blocks Ca 2ϩ extrusion and that NCLX-mediated mitochondrial Ca 2ϩ transport is inhibited by the NCX blocker CGP-37157.…”

Section: Inner Mitochondrial Membranementioning

confidence: 99%

The Mitochondrial Calcium Uniporter (MCU): Molecular Identity and Physiological Roles

Patrón

Raffaello

Granatiero

et al. 2013

Journal of Biological Chemistry

152

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The direct measurement of mitochondrial [Ca 2؉ ] with highly specific probes demonstrated that major swings in organellar [Ca 2؉ ] parallel the changes occurring in the cytosol and regulate processes as diverse as aerobic metabolism and cell death by necrosis and apoptosis. Despite great biological relevance, insight was limited by the complete lack of molecular understanding. The situation has changed, and new perspectives have emerged following the very recent identification of the mitochondrial Ca 2؉ uniporter, the channel allowing rapid Ca 2؉ accumulation across the inner mitochondrial membrane.

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NCLX is an essential component of mitochondrial Na ⁺ /Ca ²⁺ exchange

Cited by 702 publications

References 36 publications

Parallel adaptive feedback enhances reliability of the Ca ²⁺ signaling system

Parallel adaptive feedback enhances reliability of the Ca ²⁺ signaling system

CAX‐ing a wide net: Cation/H⁺ transporters in metal remediation and abiotic stress signalling

The Mitochondrial Calcium Uniporter (MCU): Molecular Identity and Physiological Roles

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NCLX is an essential component of mitochondrial Na + /Ca 2+ exchange

Cited by 702 publications

References 36 publications

Parallel adaptive feedback enhances reliability of the Ca 2+ signaling system

Parallel adaptive feedback enhances reliability of the Ca 2+ signaling system

CAX‐ing a wide net: Cation/H+ transporters in metal remediation and abiotic stress signalling

The Mitochondrial Calcium Uniporter (MCU): Molecular Identity and Physiological Roles

Contact Info

Product

Resources

About

NCLX is an essential component of mitochondrial Na ⁺ /Ca ²⁺ exchange

Parallel adaptive feedback enhances reliability of the Ca ²⁺ signaling system

Parallel adaptive feedback enhances reliability of the Ca ²⁺ signaling system

CAX‐ing a wide net: Cation/H⁺ transporters in metal remediation and abiotic stress signalling