ZnR/GPR39 regulates hepatic insulin signaling, tunes liver bioenergetics and ROS production, and mitigates liver fibrosis and injury.

Adequate supply of zinc is essential for hepatic function and its deficiency is associated with acute liver injury (ALI) and chronic nonalcoholic fatty liver disease (NAFLD). However, how zinc controls hepatic function is unknown. We found that the zinc sensitive ZnR/GPR39, a mediator of zinc signaling, enhances hepatic phosphorylation of ERK1/2, which is reduced in ZnR/GPR39 deficient livers.

Mfn2 induces NCLX-mediated calcium release from mitochondria.

Mfn2 is a mitochondrial outer membrane fusion protein with the additional role of tethering mitochondria to the ER. Here, we describe a novel connection between Mfn2 and calcium release from mitochondria. We show that Mfn2 controls the mitochondrial inner membrane sodium-calcium exchange protein NCLX, which is a major source for calcium release from mitochondria.

NCLX controls hepatic mitochondrial Ca extrusion and couples hormone-mediated mitochondrial Ca oscillations with gluconeogenesis.

Objective: Hepatic Ca signaling has been identified as a crucial key factor in driving gluconeogenesis. The involvement of mitochondria in hormone-induced Ca signaling and their contribution to metabolic activity remain, however, poorly understood. Moreover, the molecular mechanism governing the mitochondrial Ca efflux signaling remains unresolved.

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

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.

CKII Control of Axonal Plasticity Is Mediated by Mitochondrial Ca via Mitochondrial NCLX.

Mitochondrial Ca efflux by NCLX is a critical rate-limiting step in mitochondria signaling. We previously showed that NCLX is phosphorylated at a putative Casein Kinase 2 (CKII) site, the serine 271 (S271). Here, we asked if NCLX is regulated by CKII and interrogated the physiological implications of this control.

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

Impaired phosphodiesterase (PDE) function and mitochondrial Ca (i.e., [Ca]m) lead to multiple health syndromes by an unknown pathway.

Protein mishandling and impaired lysosomal proteolysis generated through calcium dysregulation in Alzheimer's disease.

Impairments in neural lysosomal- and autophagic-mediated degradation of cellular debris contribute to neuritic dystrophy and synaptic loss. While these are well-characterized features of neurodegenerative disorders such as Alzheimer's disease (AD), the upstream cellular processes driving deficits in pathogenic protein mishandling are less understood. Using a series of fluorescent biosensors and optical imaging in model cells, AD mouse models and human neurons derived from AD patients, we reveal a previously undescribed cellular signaling cascade underlying protein mishandling mediated by intracellular calcium dysregulation, an early component of AD pathogenesis.

ASIC1a senses lactate uptake to regulate metabolism in neurons.

Lactate is a major metabolite largely produced by astrocytes that nourishes neurons. ASIC1a, a Na and Ca-permeable channel with an extracellular proton sensing domain, is thought to be activated by lactate through chelation of divalent cations, including Ca, Mg and Zn, that block the channel pore. Here, by monitoring lactate-evoked H and Ca transport in cultured mouse cortical and hippocampal neurons, we find that stereo-selective neuronal uptake of L-lactate results in rapid intracellular acidification that triggers H extrusion to activate plasma membrane ASIC1a channels, leading to propagating Ca waves into the cytosol and mitochondria.

Frequency- and spike-timing-dependent mitochondrial Ca signaling regulates the metabolic rate and synaptic efficacy in cortical neurons.

Mitochondrial activity is crucial for the plasticity of central synapses, but how the firing pattern of pre- and postsynaptic neurons affects the mitochondria remains elusive. We recorded changes in the fluorescence of cytosolic and mitochondrial Ca indicators in cell bodies, axons, and dendrites of cortical pyramidal neurons in mouse brain slices while evoking pre- and postsynaptic spikes. Postsynaptic spike firing elicited fast mitochondrial Ca responses that were about threefold larger in the somas and apical dendrites than in basal dendrites and axons.

The ZIP3 Zinc Transporter Is Localized to Mossy Fiber Terminals and Is Required for Kainate-Induced Degeneration of CA3 Neurons.

Tight regulation of neuronal Zn is critical for physiological function. Multiple Zn transporters are expressed in the brain, yet their spatial distribution and distinct roles are largely unknown. Here, we show developmental regulation of the expression of Zn transporters ZIP1 and ZIP3 in mouse hippocampal neurons, corresponding to previously described increase in neuronal vesicular Zn during the first postnatal month.

SNAP23 regulates KCC2 membrane insertion and activity following mZnR/GPR39 activation in hippocampalneurons.

Modulation of the neuronal K/Cl cotransporter 2 (KCC2) activity, which mediates Cl export, is critical to neuronal function. Here, we demonstrate that KCC2 interacts with the SNARE protein synaptosome-associated protein 23, SNAP23, an essential component of membrane insertion machinery. Using KCC2 truncated mutants, we show that KCC2 C-terminal domain is essential for membrane targeting and SNAP23-dependent upregulation of KCC2 activity triggered by activation of the Zn-sensitive receptor mZnR/GPR39 in HEK293 cells.

Disrupted expression of mitochondrial NCLX sensitizes neuroglial networks to excitotoxic stimuli and renders synaptic activity toxic.

The mitochondrial solute carrier family 8 sodium/calcium/lithium exchanger, member B1 (NCLX) is an important mediator of calcium extrusion from mitochondria. In this study, we tested the hypothesis that physiological expression levels of NCLX are essential for maintaining neuronal resilience in the face of excitotoxic challenge. Using an shRNA-mediated approach, we showed that reduced NCLX expression exacerbates neuronal mitochondrial calcium dysregulation, mitochondrial membrane potential (ΔΨ) breakdown, and reactive oxygen species generation during excitotoxic stimulation of primary hippocampal cultures.

ZnT1 is a neuronal Zn/Ca exchanger.

Zinc transporter 1 (ZnT1; SLC30A1) is present in the neuronal plasma membrane, critically modulating NMDA receptor function and Zn neurotoxicity. The mechanism mediating Zn transport by ZnT1, however, has remained elusive. Here, we investigated ZnT1-dependent Zn transport by measuring intracellular changes of this ion using the fluorescent indicator FluoZin-3.

Aberrant activity of mitochondrial NCLX is linked to impaired synaptic transmission and is associated with mental retardation.

Calcium dynamics control synaptic transmission. Calcium triggers synaptic vesicle fusion, determines release probability, modulates vesicle recycling, participates in long-term plasticity and regulates cellular metabolism. Mitochondria, the main source of cellular energy, serve as calcium signaling hubs.

Sprinkling salt on mitochondria: The metabolic and pathophysiological roles of mitochondrial Na signaling mediated by NCLX.

NCLX, the mitochondrial Na/Ca transporter is a key player in Ca signaling. However, its role in Na signaling is poorly understood. In this review we focus on Na signaling by NCLX, and discuss recent physiological and pathophysiological roles attributed to the Na influx into mitochondria.

Recent studies on NCLX in health and diseases.

The mitochondria is a major hub for cellular Ca 2+ signaling. The identification of MCU, the mitochondrial Ca 2+ influx mediator, and the mitochondrial Ca 2+ extruder NCLX, were major breakthroughs in this field. Their identification provided novel molecular tools and animal models to interrogate their physiological function and mode of regulation.

ZnR/GPR39 controls cell migration by orchestrating recruitment of KCC3 into protrusions, re-organization of actin and activation of MMP.

Actin re-organization and degradation of extracellular matrix by metalloproteases (MMPs) facilitate formation of cellular protrusions that are required for cell proliferation and migration. We find that Zn activation of the Gq-coupled receptor ZnR/GPR39 controls these processes by regulating K/Cl co-transporter KCC3, which modulates cell volume. Silencing of KCC3 expression or activity reverses ZnR/GPR39 enhancement of cell proliferation, migration and invasion through Matrigel.

Differential signaling patterns of stimulated bone marrow-derived dendritic cells under α1-antitrypsin-enriched conditions.

Dendritic cells (DCs) mature upon an inflammatory trigger. However, an inflammatory trigger can lead to a semi-mature phenotype, allowing DCs to evoke tolerance and expedite the resolution of inflammation. This duality likely involves context-dependent modulation of inflammatory signaling.

Dichotomous role of the human mitochondrial Na/Ca2/Li exchanger NCLX in colorectal cancer growth and metastasis.

Despite the established role of mitochondria in cancer, the mechanisms by which mitochondrial Ca (mtCa) regulates tumorigenesis remain incompletely understood. The crucial role of mtCa in tumorigenesis is highlighted by altered expression of proteins mediating mtCa uptake and extrusion in cancer. Here, we demonstrate decreased expression of the mitochondrial Na/Ca/Li exchanger NCLX () in human colorectal tumors and its association with advanced-stage disease in patients.

Novel humanin analogs confer neuroprotection and myoprotection to neuronal and myoblast cell cultures exposed to ischemia-like and doxorubicin-induced cell death insults.

Humanin (HN) is a 24-amino acid mitochondrial-derived peptide, best known for its ability to protect neurons from damage caused by ischemic stroke and neurodegenerative insults and cardiomyocytes from myocardial infarction or doxorubicin (Dox)-induced cardiotoxicity. This study examines the neuroprotective and myoprotective effects of HN novel synthetic analogs HUJInin and c(D-Ser14-HN), prepared by solid-phase peptide synthesis. The cellular models employed were oxygen-glucose-deprivation (OGD) followed by reoxygenation (R)-induced neurotoxicity in PC12 and SH-SY5Y neuronal cell cultures and Dox-induced cardiotoxicity in H9c2 and C2C12 myoblast cell cultures, respectively.

NCLX prevents cell death during adrenergic activation of the brown adipose tissue.

A sharp increase in mitochondrial Ca marks the activation of brown adipose tissue (BAT) thermogenesis, yet the mechanisms preventing Ca deleterious effects are poorly understood. Here, we show that adrenergic stimulation of BAT activates a PKA-dependent mitochondrial Ca extrusion via the mitochondrial Na/Ca exchanger, NCLX. Adrenergic stimulation of NCLX-null brown adipocytes (BA) induces a profound mitochondrial Ca overload and impaired uncoupled respiration.

Klotho rewires cellular metabolism of breast cancer cells through alteration of calcium shuttling and mitochondrial activity.

Klotho is a transmembrane protein, which can be shed and act as a circulating hormone and is involved in regulating cellular calcium levels and inhibition of the PI3K/AKT pathway. As a longevity hormone, it protects normal cells from oxidative stress, and as a tumor suppressor it inhibits growth of cancer cells. Mechanisms governing these differential activities have not been addressed.