In vitro aging promotes endoplasmic reticulum (ER)-mitochondria Ca 2+ cross talk and loss of store-operated Ca 2+ entry (SOCE) in rat hippocampal neurons

Calvo-Rodríguez, María; García-Durillo, Mónica; Alonso, Carlos; Núñez, Lucı́a

doi:10.1016/j.bbamcr.2016.08.001

Cited by 69 publications

(81 citation statements)

References 42 publications

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“…Andersson et al ., ; Cooper et al ., ), which increases the leak of calcium into the cytosol and increases calcium overload of mitochondria. Calcium overload of the matrix is also reported to be enhanced by increased direct transfer of calcium from ER to mitochondria (Calvo‐Rodriguez et al ., ). In addition, aging downregulates the expression of the calcium buffering proteins regucalcin (Vaz et al ., ) and FKBP1b (Gant et al ., ).…”

Section: Disruption Of Calcium Homeostasis In Aging Increases the Frementioning

confidence: 97%

The path from mitochondrial ROS to aging runs through the mitochondrial permeability transition pore

Rottenberg¹,

2017

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SummaryExcessive production of mitochondrial reactive oxygen species (mROS) is strongly associated with mitochondrial and cellular oxidative damage, aging, and degenerative diseases. However, mROS also induces pathways of protection of mitochondria that slow aging, inhibit cell death, and increase lifespan. Recent studies show that the activation of the mitochondrial permeability transition pore (mPTP), which is triggered by mROS and mitochondrial calcium overloading, is enhanced in aged animals and humans and in aging‐related degenerative diseases. mPTP opening initiates further production and release of mROS that damage both mitochondrial and nuclear DNA, proteins, and phospholipids, and also releases matrix NAD that is hydrolyzed in the intermembrane space, thus contributing to the depletion of cellular NAD that accelerates aging. Oxidative damage to calcium transporters leads to calcium overload and more frequent opening of mPTP. Because aging enhances the opening of the mPTP and mPTP opening accelerates aging, we suggest that mPTP opening drives the progression of aging. Activation of the mPTP is regulated, directly and indirectly, not only by the mitochondrial protection pathways that are induced by mROS, but also by pro‐apoptotic signals that are induced by DNA damage. We suggest that the integration of these contrasting signals by the mPTP largely determines the rate of cell aging and the initiation of cell death, and thus animal lifespan. The suggestion that the control of mPTP activation is critical for the progression of aging can explain the conflicting and confusing evidence regarding the beneficial and deleterious effects of mROS on health and lifespan.

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Section: Disruption Of Calcium Homeostasis In Aging Increases the Frementioning

confidence: 97%

The path from mitochondrial ROS to aging runs through the mitochondrial permeability transition pore

Rottenberg¹,

2017

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“…Alterations of Ca 2+ signaling have emerged to an important factor in cancer progression [7,8]. Store-operated calcium entry (SOCE), a major Ca 2+ influx mechanism activated upon Ca 2+ storage depletion, is a ubiquitous mechanism for Ca 2+ influx in nonexcitable cells [9], while stromal interaction molecule 1 (STIM1) is a calcium sensor predominantly localized in the endoplasmic reticulum (ER). STIM1 interacts with Orail, which is identified as the major store-operated Ca 2+ channel (SOC) in the plasma membrane, and initiate SOCE and refill of intracellular Ca 2+ stores [10].…”

Section: Introductionmentioning

confidence: 99%

Knockdown of STIM1 expression inhibits non-small-cell lung cancer cell proliferation in vitro and in nude mouse xenografts

Zeng

et al. 2019

Bioengineered

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Stromal interaction molecule 1 (STIM1) is a calcium-sensing protein localized in the membrane of the endoplasmic reticulum. The expression of STIM1 has been shown to be closely associated with cell proliferation. The aim of the present study was to investigate the role of STIM1 in the regulation of cancer progression and its clinical relevance. The data demonstrated that the expression of the STIM1 was significantly higher in non-small-cell lung cancer (NSCLC) tissues than in benign lesions and was associated with advanced NSCLC T stage. Knockdown of STIM1 expression in NSCLC cell lines A549 and SK-MES-1 significantly inhibited cell proliferation and induces A549 and SK-MES-1 cell arrest at the G2/M and S phases of the cell cycle. Western blotting showed that the expression of cyclin-dependent kinase (CDK) 1 and CDK2 were reduced while knockdown of STIM1 expression. Furthermore, knockdown of STIM1 in NSCLC cells significantly reduced the levels of xenograft tumor growth in nude mice. These data indicate that aberrant expression of the STIM1 protein may contribute to NSCLC progression. Future studies should focus on targeting STIM1 as a novel strategy for NSCLC therapy.

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“…To examine the effects of L-CS on neuronal aging, experiments were performed in long-term culture of primary cortical neurons (hereafter termed 'aged' neurons ) used here as an in vitro model of neuronal senescence [21][22][23] . Cultures were maintained for 18-19 days in vitro (DIV) and then treated with L-CS (30 µM) or vehicle (serum-free medium) for an additional three days.…”

Section: Resultsmentioning

confidence: 99%

Inhibition ofde novoceramide biosynthesis affects aging phenotype in anin vitromodel of neuronal senescence

Granzotto

Bomba

Castelli

et al. 2019

Preprint

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Although aging is considered to be an unavoidable event, recent experimental evidence suggests that the process can be delayed, counteracted, if not completely interrupted. Aging is the primary risk factor for the onset and development of neurodegenerative conditions like Alzheimer's disease, Parkinson's disease, and Amyotrophic Lateral Sclerosis. Intracellular calcium (Ca 2+ i) dyshomeostasis, mitochondrial dysfunction, oxidative stress, and lipid dysregulation are critical factors that contribute to senescence-related processes. Ceramides, a class of sphingolipids involved in a wide array of biological functions, are important mediators of cellular senescence, but their role in neuronal aging is still largely unexplored.In this study, we investigated the effects of L-cycloserine (L-CS), an inhibitor of de novo ceramide biosynthesis, on the aging phenotype of cortical neurons that have been maintained in culture for 22 days, a setting employed as an in vitro model of cellular senescence. Our findings indicate that 'aged' neurons display, when compared to control cultures, overt dysregulation of cytosolic and subcellular [Ca 2+ ]i levels, mitochondrial dysfunction, increased reactive oxygen species generation, altered synaptic activity as well as the activation of neuronal death-related molecules. Treatment with L-CS (30 µM) positively affected the senescent phenotype, a result accompanied by recovery of neuronal [Ca 2+ ]i signaling, and reduction of mitochondrial dysfunction and reactive oxygen species generation.The results suggest that the de novo ceramide biosynthesis may represent a critical intermediate in the molecular and functional cascade leading to neuronal senescence. Our findings also identify ceramide biosynthesis inhibitors as promising pharmacological tools to decrease agerelated neuronal dysfunctions. L-CS treatment does not modify NCX activityCeramides can modulate the activity of the plasmalemmal Na + -Ca 2+ exchanger (NCX) 25 , a low capacitance high-affinity system that critically regulates cellular [Ca 2+ ]i. We, therefore, investigated

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In vitro aging promotes endoplasmic reticulum (ER)-mitochondria Ca 2+ cross talk and loss of store-operated Ca 2+ entry (SOCE) in rat hippocampal neurons

Abstract: Aging is associated to cognitive decline and susceptibility to neuron death, two processes related recently to subcellular Ca 2+ homeostasis. Memory storage relies on mushroom spines stability that depends on store-operated

Cited by 69 publications

References 42 publications

The path from mitochondrial ROS to aging runs through the mitochondrial permeability transition pore

The path from mitochondrial ROS to aging runs through the mitochondrial permeability transition pore

Knockdown of STIM1 expression inhibits non-small-cell lung cancer cell proliferation in vitro and in nude mouse xenografts

Inhibition ofde novoceramide biosynthesis affects aging phenotype in anin vitromodel of neuronal senescence

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