Essential role of the mitochondrial Na+/Ca2+ exchanger NCLX in mediating PDE2-dependent neuronal survival and learning

Rozenfeld, Maya; Azoulay, Ivana Savic; Nissim, Tsipi Ben Kasus; Stavsky, Alexandra; Melamed, Moran; Stutzmann, Grace E.; Hershfinkel, Michal; Kofman, Ora; Sekler, Israel

doi:10.1016/j.celrep.2022.111772

Cited by 11 publications

(9 citation statements)

References 61 publications

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“…Previous studies indicated that mitochondrial Ca 2+ influx by MCU is downregulated by even a subtle rise in mitochondrial free Ca 2+ , a process that is tuned by EMRE and Micu1 (32)(33)(34)(35). Consistent with these findings, mitochondrial Ca 2+ oscillations are triggered by caffeine in neurons and are suppressed by NCLX KO, which causes mitochondrial Ca 2+ overload (36).…”

Section: Discussionsupporting

confidence: 66%

NCLX controls hepatic mitochondrial Ca²⁺extrusion and couples hormone-mediated mitochondrial Ca²⁺oscillations with gluconeogenesis

Taha,

Assali,

Stuzmann

et al. 2024

Preprint

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Hepatic Ca2+ signaling is emerging as a key factor in mediating gluconeogenesis. However, the identity of the hepatic mitochondrial Ca2+ transporter is controversial and the role of mitochondria in controlling hormonal Ca2+ signaling and linking them to metabolic activity is poorly understood. We first interrogated the role of the mitochondrial Na+/Ca2+ exchanger NCLX by triggering cytosolic Ca2+ purinergic signaling in primary hepatocytes, and Ca2+ responses in isolated mitochondria from WT, global NCLX KO, and conditional hepatic NCLX KO mice models. We monitored a higher rate of Na+-dependent mitochondrial Ca2+ efflux in NCLX-expressing hepatocytes, indicating that it constitutes the major Ca2+ efflux pathway. We then asked if NCLX is controlling the hormone-dependent mitochondrial Ca2+ oscillations by employing physiological concentrations of glucagon and vasopressin. Consistent with previous studies, hormone applications triggered mitochondrial Ca2+ oscillations in WT hepatocytes. In NCLX KO hepatocytes the cytosolic oscillations persisted, however, the mitochondrial Ca2+ oscillations were suppressed. To further understand the metabolic role of NCLX in the hepatic system, we examined gluconeogenic function in vivo and ex vitro by monitoring hepatic glucose production. We found that blood glucose dropped faster in the conditional KO mice and their hepatic glucagon-dependent glucose production was reduced, indicating that gluconeogenesis was impaired in hepatic conditional NCLX KO mice. Taken together, our results indicate that NCLX is the primary Ca2+ extruder in hepatocytes and is required for mediating the hormone-dependent mitochondrial Ca2+ oscillations and gluconeogenesis.

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Section: Discussionsupporting

confidence: 66%

NCLX controls hepatic mitochondrial Ca²⁺extrusion and couples hormone-mediated mitochondrial Ca²⁺oscillations with gluconeogenesis

Taha,

Assali,

Stuzmann

et al. 2024

Preprint

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Section: Strategies Targeting Processes Related To Mitochondrial Ca 2+mentioning

confidence: 99%

“…One approach to reduce mitochondrial Ca 2+ accumulation is to enhance the efflux pathway through NCLX. NCLX has been related to maintaining neuronal health and learning, and protects neurons from excitotoxic insults (Hagenston et al., 2022; Rozenfeld et al., 2022) such as the glutamate excitotoxicity seen in ALS. Loss of NCLX is detected in models of Alzheimer's disease and genetic restoration of NCLX expression relieved Alzheimer's disease‐related pathology (Jadiya et al., 2023).…”

Section: Introductionmentioning

confidence: 99%

Targeting mitochondrial Ca²⁺ uptake for the treatment of amyotrophic lateral sclerosis

Zhong,

Rua,

Wei‐LaPierre

2023

The Journal of Physiology

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Amyotrophic lateral sclerosis (ALS) is a rare adult‐onset neurodegenerative disease characterized by progressive motor neuron (MN) loss, muscle denervation and paralysis. Over the past several decades, researchers have made tremendous efforts to understand the pathogenic mechanisms underpinning ALS, with much yet to be resolved. ALS is described as a non‐cell autonomous condition with pathology detected in both MNs and non‐neuronal cells, such as glial cells and skeletal muscle. Studies in ALS patient and animal models reveal ubiquitous abnormalities in mitochondrial structure and function, and disturbance of intracellular calcium homeostasis in various tissue types, suggesting a pivotal role of aberrant mitochondrial calcium uptake and dysfunctional calcium signalling cascades in ALS pathogenesis. Calcium signalling and mitochondrial dysfunction are intricately related to the manifestation of cell death contributing to MN loss and skeletal muscle dysfunction. In this review, we discuss the potential contribution of intracellular calcium signalling, particularly mitochondrial calcium uptake, in ALS pathogenesis. Functional consequences of excessive mitochondrial calcium uptake and possible therapeutic strategies targeting mitochondrial calcium uptake or the mitochondrial calcium uniporter, the main channel mediating mitochondrial calcium influx, are also discussed. image

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“…We have shown that the NCLX mediates the extrusion of Ca 2+ from mitochondria (Palty et al, 2010) and identified drugs that oppose injurious mitochondrial Ca 2+ overloading in neurons by increasing NCLX activity (Rozenfeld et al, 2022). To appreciate how the NCLX can be targeted to enhance mitochondrial Ca 2+ efflux, it is necessary to describe the structural and functional features of this Na + /Ca 2+ exchanger.…”

Section: Structure and Function Of The Sodium/ca 2+ /Lithium Exchange...mentioning

confidence: 99%

“…To this end, we have shown that mitochondrial Ca 2+ uptake and efflux in the brain are mediated by the mitochondrial Ca 2+ uniporter complex (MCU cx ) and sodium/Ca 2+ /lithium exchanger (NCLX), respectively (Palty et al, 2010;Nichols et al, 2017). These important findings led to our recent studies demonstrating that MCU cx inhibition and NCLX activation potently protect neurons from ischemic/reperfusion injury (Nichols et al, 2018;Novorolsky et al, 2020) and excitotoxicity (Rozenfeld et al, 2022) thought to drive stroke-related brain damage (Choi, 1992;Eltzschig and Eckle, 2011). Based on these studies, we describe the combined use of drugs that block the MCU cx and stimulate the NCLX to protect the NVU after an ischemic or hemorrhagic stroke.…”

Section: Introductionmentioning

confidence: 99%

Preserving and enhancing mitochondrial function after stroke to protect and repair the neurovascular unit: novel opportunities for nanoparticle-based drug delivery

Novorolsky

Kasheke

Hakim

et al. 2023

Front. Cell. Neurosci.

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The neurovascular unit (NVU) is composed of vascular cells, glia, and neurons that form the basic component of the blood brain barrier. This intricate structure rapidly adjusts cerebral blood flow to match the metabolic needs of brain activity. However, the NVU is exquisitely sensitive to damage and displays limited repair after a stroke. To effectively treat stroke, it is therefore considered crucial to both protect and repair the NVU. Mitochondrial calcium (Ca2+) uptake supports NVU function by buffering Ca2+ and stimulating energy production. However, excessive mitochondrial Ca2+ uptake causes toxic mitochondrial Ca2+ overloading that triggers numerous cell death pathways which destroy the NVU. Mitochondrial damage is one of the earliest pathological events in stroke. Drugs that preserve mitochondrial integrity and function should therefore confer profound NVU protection by blocking the initiation of numerous injury events. We have shown that mitochondrial Ca2+ uptake and efflux in the brain are mediated by the mitochondrial Ca2+ uniporter complex (MCUcx) and sodium/Ca2+/lithium exchanger (NCLX), respectively. Moreover, our recent pharmacological studies have demonstrated that MCUcx inhibition and NCLX activation suppress ischemic and excitotoxic neuronal cell death by blocking mitochondrial Ca2+ overloading. These findings suggest that combining MCUcx inhibition with NCLX activation should markedly protect the NVU. In terms of promoting NVU repair, nuclear hormone receptor activation is a promising approach. Retinoid X receptor (RXR) and thyroid hormone receptor (TR) agonists activate complementary transcriptional programs that stimulate mitochondrial biogenesis, suppress inflammation, and enhance the production of new vascular cells, glia, and neurons. RXR and TR agonism should thus further improve the clinical benefits of MCUcx inhibition and NCLX activation by increasing NVU repair. However, drugs that either inhibit the MCUcx, or stimulate the NCLX, or activate the RXR or TR, suffer from adverse effects caused by undesired actions on healthy tissues. To overcome this problem, we describe the use of nanoparticle drug formulations that preferentially target metabolically compromised and damaged NVUs after an ischemic or hemorrhagic stroke. These nanoparticle-based approaches have the potential to improve clinical safety and efficacy by maximizing drug delivery to diseased NVUs and minimizing drug exposure in healthy brain and peripheral tissues.

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Essential role of the mitochondrial Na+/Ca2+ exchanger NCLX in mediating PDE2-dependent neuronal survival and learning

Cited by 11 publications

References 61 publications

NCLX controls hepatic mitochondrial Ca²⁺extrusion and couples hormone-mediated mitochondrial Ca²⁺oscillations with gluconeogenesis

NCLX controls hepatic mitochondrial Ca²⁺extrusion and couples hormone-mediated mitochondrial Ca²⁺oscillations with gluconeogenesis

Targeting mitochondrial Ca²⁺ uptake for the treatment of amyotrophic lateral sclerosis

Preserving and enhancing mitochondrial function after stroke to protect and repair the neurovascular unit: novel opportunities for nanoparticle-based drug delivery

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Essential role of the mitochondrial Na+/Ca2+ exchanger NCLX in mediating PDE2-dependent neuronal survival and learning

Cited by 11 publications

References 61 publications

NCLX controls hepatic mitochondrial Ca2+extrusion and couples hormone-mediated mitochondrial Ca2+oscillations with gluconeogenesis

NCLX controls hepatic mitochondrial Ca2+extrusion and couples hormone-mediated mitochondrial Ca2+oscillations with gluconeogenesis

Targeting mitochondrial Ca2+ uptake for the treatment of amyotrophic lateral sclerosis

Preserving and enhancing mitochondrial function after stroke to protect and repair the neurovascular unit: novel opportunities for nanoparticle-based drug delivery

Contact Info

Product

Resources

About

NCLX controls hepatic mitochondrial Ca²⁺extrusion and couples hormone-mediated mitochondrial Ca²⁺oscillations with gluconeogenesis

NCLX controls hepatic mitochondrial Ca²⁺extrusion and couples hormone-mediated mitochondrial Ca²⁺oscillations with gluconeogenesis

Targeting mitochondrial Ca²⁺ uptake for the treatment of amyotrophic lateral sclerosis