NCLX Protein, but Not LETM1, Mediates Mitochondrial Ca2+ Extrusion, Thereby Limiting Ca2+-induced NAD(P)H Production and Modulating Matrix Redox State

Marchi, Umberto De; Santo‐Domingo, Jaime; Castelbou, Cyril; Sekler, Israel; Wiederkehr, Andreas; Demaurex, Nicolas

doi:10.1074/jbc.m113.540898

Cited by 102 publications

(91 citation statements)

References 70 publications

(68 reference statements)

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“…Ca 2+ levels within mitochondria are further regulated by Ca 2+ efflux carried out by the mitochondrial Na + /Ca 2+ Exchanger (termed NCLX for its ability to exchange both Na + and Li + for Ca 2+ ) [261] and the mitochondria Permeability Transition Pore (mPTP) [262]. Mitochondrial Ca 2+ homeostasis is fine-tuned by the activity of NCLX which extrudes Ca 2+ from mitochondria into the cytosol, and in turn aids in maintaining mitochondrial redox homeostasis [263]. …”

Section: Redox Regulation Of Er and Mitochondrial Ca2+ Modulatorsmentioning

confidence: 99%

Crosstalk between calcium and reactive oxygen species signaling in cancer

2017

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The interplay between Ca2+ and reactive oxygen species (ROS) signaling pathways is well established, with reciprocal regulation occurring at a number of subcellular locations. Many Ca2+ channels at the cell surface and intracellular organelles, including the endoplasmic reticulum and mitochondria are regulated by redox modifications. In turn, Ca2+ signaling can influence the cellular generation of ROS, from sources such as NADPH oxidases and mitochondria. This relationship has been explored in great depth during the process of apoptosis, where surges of Ca2+ and ROS are important mediators of cell death. More recently, coordinated and localized Ca2+ and ROS transients appear to play a major role in a vast variety of pro-survival signaling pathways that may be crucial for both physiological and pathophysiological functions. While much work is required to firmly establish this Ca2+-ROS relationship in cancer, existing evidence from other disease models suggests this crosstalk is likely of significant importance in tumorigenesis. In this review, we describe the regulation of Ca2+ channels and transporters by oxidants and discuss the potential consequences of the ROS-Ca2+ interplay in tumor cells.

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Section: Redox Regulation Of Er and Mitochondrial Ca2+ Modulatorsmentioning

confidence: 99%

Crosstalk between calcium and reactive oxygen species signaling in cancer

2017

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“…In particular, the Na + -dependent mechanism is universally accepted to be mediated by NCLX9, while the molecular identity of the H + /Ca 2+ antiporter is still controversial10,11, although several lines of evidence suggest that Letm1 can play a role in this pathway12–14. Conversely, the MCU complex includes integral components of the inner mitochondrial membrane, namely MCU15,16, MCUb17 and EMRE18, and associated regulators localized in the intermembrane space, i.e.…”

Section: Introductionmentioning

confidence: 99%

MICU3 is a tissue-specific enhancer of mitochondrial calcium uptake

et al. 2018

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The versatility and universality of Ca2+ as intracellular messenger is guaranteed by the compartmentalization of changes in [Ca2+]. In this context, mitochondrial Ca2+ plays a central role, by regulating both specific organelle functions and global cellular events. This versatility is also guaranteed by a cell type-specific Ca2+ signaling toolkit controlling specific cellular functions. Accordingly, mitochondrial Ca2+ uptake is mediated by a multimolecular structure, the MCU complex, which differs among various tissues. Its activity is indeed controlled by different components that cooperate to modulate specific channeling properties. We here investigate the role of MICU3, an EF-hand containing protein expressed at high levels especially in brain. We show that MICU3 forms a disulfide bond-mediated dimer with MICU1, but not with MICU2, and it acts as enhancer of MCU-dependent mitochondrial Ca2+ uptake. Silencing of MICU3 in primary cortical neurons impairs Ca2+ signals elicited by synaptic activity, thus suggesting a specific role in regulating neuronal function.

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“…This group presents that NCLX is the mediator of calcium extrusion from the mitochondria, not Letm1, and support the idea that NCLX has a protective function by standardizing NAD(P)H production and regulating ROS. Increased mtCa 2+ showed increased auto-fluorescence of NAD(P)H, which was drastically diminished by NCLX overexpression (53).…”

Section: Mitochondria and Heart Failurementioning

confidence: 99%

Epigenetic revival of a dead cardiomyocyte through mitochondrial interventions

Kunkel¹,

Chaturvedi²,

Tyagi³

2015

Biomolecular Concepts

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Mitochondrial dysfunction has been reported to underline heart failure, and our earlier report suggests that mitochondrial fusion and fission contributes significantly to volume overload heart failure. Although ample studies highlight mitochondrial dysfunction to be a major cause, studies are lacking to uncover the role of mitochondrial epigenetics, i.e. epigenetic modifications of mtDNA in cardiomyocyte function. Additionally, mitochondrial proteases like calpain and Lon proteases are underexplored. Cardiomyopathies are correlated to mitochondrial damage via increased reactive oxygen species production and free calcium within cardiomyocytes. These abnormalities drive increased proteolytic activity from matrix metalloproteinases and calpains, respectively. These proteases degrade the cytoskeleton of the cardiomyocyte and lead to myocyte death. mtDNA methylation is another factor that can lead to myocyte death by silencing several genes of mitochondria or upregulating the expression of mitochondrial proteases by hypomethylation. Cardiomyocyte resuscitation can occur through mitochondrial interventions by decreasing the proteolytic activity and reverting back the epigenetic changes in the mtDNA which lead to myocyte dysfunction. Epigenetic changes in the mtDNA are triggered by environmental factors like pollution and eating habits with cigarette smoking. An analysis of mitochondrial epigenetics in cigarette-smoking mothers will reveal an underlying novel mechanism leading to mitochondrial dysfunction and eventually heart failure. This review is focused on the mitochondrial dysfunction mechanisms that can be reverted back to resuscitate cardiomyocytes.

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NCLX Protein, but Not LETM1, Mediates Mitochondrial Ca2+ Extrusion, Thereby Limiting Ca2+-induced NAD(P)H Production and Modulating Matrix Redox State

Cited by 102 publications

References 70 publications

Crosstalk between calcium and reactive oxygen species signaling in cancer

Crosstalk between calcium and reactive oxygen species signaling in cancer

MICU3 is a tissue-specific enhancer of mitochondrial calcium uptake

Epigenetic revival of a dead cardiomyocyte through mitochondrial interventions

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