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Ca2+ Signaling and Mitochondrial Function in Neurodegenerative Diseases
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Ca2+ Signaling and Mitochondrial Function in Neurodegenerative Diseases

A topical collection in Cells (ISSN 2073-4409). This collection belongs to the section "Intracellular and Plasma Membranes".

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Editors

Dr. Ghanim Ullah

E-Mail Website
Collection Editor
Department of Physics, University of South Florida, Tampa, FL 33647, USA
Interests: calcium signaling; mitochondrial function; neurodegenerative diseases; ion channel modeling; ion concentration dynamics; epileptic seizures; spreading depolarization
Dr. Angelo Demuro

E-Mail Website
Collection Editor
Department of Neurobiology and Behavior, University of California, Irvine, CA 92697, USA
Interests: calcium signaling; mitochondrial function; neurodegenerative diseases; cytotoxicity; ion channel function; fluorescence microscopy; electrophysiology

Topical Collection Information

Dear Colleagues,

Ca2+ is a ubiquitous second messenger that regulates numerous cell processes, such as synaptic function, memory formation, bioenergetics, and gene transcription. The universality and specificity of Ca2+ signaling stem from its hierarchical spatiotemporal organization, ranging from single channel events to global waves sweeping the entire cell. Substantial evidence accumulated over the last three decades shows that in several neurodegenerative illnesses, including Alzheimer’s, Parkinson’s, and Huntington’s diseases, neuronal and glial Ca2+ signaling is irreversibly disrupted at all these spatiotemporal scales. The uncontrolled rise in cytosolic Ca2+ is believed to cause mitochondrial Ca2+ overload, affecting cell bioenergetics and activating signaling cascade that leads to cell death by apoptosis.

The purpose of this Topic Collection is to overview the current status of the field and highlight the new findings about the role of impaired Ca2+ homeostasis in neurodegenerative diseases and the novel experimental and computational approach now available for their investigation. Special focus will be placed on the role of intracellular oligomeric peptides and intracellular organelles in Ca2+ signaling impairments, Ca2+ mediated changes in mitochondrial function, and the feedback loop between Ca2+ disruptions, intracellular organelles, and amyloidosis.

Dr. Ghanim Ullah
Dr. Angelo Demuro
Collection Editors

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Keywords

  • neurodegenerative diseases
  • Ca2+ signaling
  • mitochondrial function
  • intracellular oligomers
  • intracellular organelles

Published Papers (6 papers)

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2022

19 pages, 2838 KiB  
Article
CKII Control of Axonal Plasticity Is Mediated by Mitochondrial Ca2+ via Mitochondrial NCLX
by Tomer Katoshevski, Lior Bar, Eliav Tikochinsky, Shimon Harel, Tsipi Ben-Kasus Nissim, Ivan Bogeski, Michal Hershfinkel, Bernard Attali and Israel Sekler
Cells 2022, 11(24), 3990; https://doi.org/10.3390/cells11243990 - 09 Dec 2022
Cited by 2 | Viewed by 1351
Abstract
Mitochondrial Ca2+ 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 [...] Read more.
Mitochondrial Ca2+ 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. We found that CKII inhibitors down-regulated NCLX-dependent Ca2+ transport activity in SH-SY5Y neuronal cells and primary hippocampal neurons. Furthermore, we show that the CKII phosphomimetic mutants on NCLX inhibited (S271A) and constitutively activated (S271D) NCLX transport, respectively, rendering it insensitive to CKII inhibition. These phosphomimetic NCLX mutations also control the allosteric regulation of NCLX by mitochondrial membrane potential (ΔΨm). Since the omnipresent CKII is necessary for modulating the plasticity of the axon initial segment (AIS), we interrogated, in hippocampal neurons, if NCLX is required for this process. Similarly to WT neurons, NCLX-KO neurons can exhibit homeostatic plasticity following M-channel block. However, while WT neurons utilize a CKII-sensitive distal relocation of AIS Na+ and Kv7 channels to decrease their intrinsic excitability, we did not observe such translocation in NCLX-KO neurons. Thus, our results indicate that NCLX is regulated by CKII and is a crucial link between CKII signaling and fast neuronal plasticity. Full article
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17 pages, 2742 KiB  
Article
Intracellular Injection of Brain Extracts from Alzheimer’s Disease Patients Triggers Unregulated Ca2+ Release from Intracellular Stores That Hinders Cellular Bioenergetics
by Anna Pensalfini, Abdul Rahim Umar, Charles Glabe, Ian Parker, Ghanim Ullah and Angelo Demuro
Cells 2022, 11(22), 3630; https://doi.org/10.3390/cells11223630 - 16 Nov 2022
Cited by 1 | Viewed by 1365
Abstract
Strong evidence indicates that amyloid beta (Aβ) inflicts its toxicity in Alzheimer’s disease (AD) by promoting uncontrolled elevation of cytosolic Ca2+ in neurons. We have previously shown that synthetic Aβ42 oligomers stimulate abnormal intracellular Ca2+ release from the endoplasmic reticulum stores, [...] Read more.
Strong evidence indicates that amyloid beta (Aβ) inflicts its toxicity in Alzheimer’s disease (AD) by promoting uncontrolled elevation of cytosolic Ca2+ in neurons. We have previously shown that synthetic Aβ42 oligomers stimulate abnormal intracellular Ca2+ release from the endoplasmic reticulum stores, suggesting that a similar mechanism of Ca2+ toxicity may be common to the endogenous Aβs oligomers. Here, we use human postmortem brain extracts from AD-affected patients and test their ability to trigger Ca2+ fluxes when injected intracellularly into Xenopus oocytes. Immunological characterization of the samples revealed the elevated content of soluble Aβ oligomers only in samples from AD patients. Intracellular injection of brain extracts from control patients failed to trigger detectable changes in intracellular Ca2+. Conversely, brain extracts from AD patients triggered Ca2+ events consisting of local and global Ca2+ fluorescent transients. Pre-incubation with either the conformation-specific OC antiserum or caffeine completely suppressed the brain extract’s ability to trigger cytosolic Ca2+ events. Computational modeling suggests that these Ca2+ fluxes may impair cells bioenergetic by affecting ATP and ROS production. These results support the hypothesis that Aβ oligomers contained in neurons of AD-affected brains may represent the toxic agents responsible for neuronal malfunctioning and death associated with the disruption of Ca2+ homeostasis. Full article
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31 pages, 3440 KiB  
Article
Upregulated Ca2+ Release from the Endoplasmic Reticulum Leads to Impaired Presynaptic Function in Familial Alzheimer’s Disease
by Temitope Adeoye, Syed I. Shah, Angelo Demuro, David A. Rabson and Ghanim Ullah
Cells 2022, 11(14), 2167; https://doi.org/10.3390/cells11142167 - 11 Jul 2022
Cited by 5 | Viewed by 2228
Abstract
Neurotransmitter release from presynaptic terminals is primarily regulated by rapid Ca2+ influx through membrane-resident voltage-gated Ca2+ channels (VGCCs). Moreover, accumulating evidence indicates that the endoplasmic reticulum (ER) is extensively present in axonal terminals of neurons and plays a modulatory role in [...] Read more.
Neurotransmitter release from presynaptic terminals is primarily regulated by rapid Ca2+ influx through membrane-resident voltage-gated Ca2+ channels (VGCCs). Moreover, accumulating evidence indicates that the endoplasmic reticulum (ER) is extensively present in axonal terminals of neurons and plays a modulatory role in synaptic transmission by regulating Ca2+ levels. Familial Alzheimer’s disease (FAD) is marked by enhanced Ca2+ release from the ER and downregulation of Ca2+ buffering proteins. However, the precise consequence of impaired Ca2+ signaling within the vicinity of VGCCs (active zone (AZ)) on exocytosis is poorly understood. Here, we perform in silico experiments of intracellular Ca2+ signaling and exocytosis in a detailed biophysical model of hippocampal synapses to investigate the effect of aberrant Ca2+ signaling on neurotransmitter release in FAD. Our model predicts that enhanced Ca2+ release from the ER increases the probability of neurotransmitter release in FAD. Moreover, over very short timescales (30–60 ms), the model exhibits activity-dependent and enhanced short-term plasticity in FAD, indicating neuronal hyperactivity—a hallmark of the disease. Similar to previous observations in AD animal models, our model reveals that during prolonged stimulation (~450 ms), pathological Ca2+ signaling increases depression and desynchronization with stimulus, causing affected synapses to operate unreliably. Overall, our work provides direct evidence in support of a crucial role played by altered Ca2+ homeostasis mediated by intracellular stores in FAD. Full article
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15 pages, 3009 KiB  
Review
Alterations of Mitochondrial Network by Cigarette Smoking and E-Cigarette Vaping
by Manasa Kanithi, Sunil Junapudi, Syed Islamuddin Shah, Alavala Matta Reddy, Ghanim Ullah and Bojjibabu Chidipi
Cells 2022, 11(10), 1688; https://doi.org/10.3390/cells11101688 - 19 May 2022
Cited by 6 | Viewed by 4126
Abstract
Toxins present in cigarette and e-cigarette smoke constitute a significant cause of illnesses and are known to have fatal health impacts. Specific mechanisms by which toxins present in smoke impair cell repair are still being researched and are of prime interest for developing [...] Read more.
Toxins present in cigarette and e-cigarette smoke constitute a significant cause of illnesses and are known to have fatal health impacts. Specific mechanisms by which toxins present in smoke impair cell repair are still being researched and are of prime interest for developing more effective treatments. Current literature suggests toxins present in cigarette smoke and aerosolized e-vapor trigger abnormal intercellular responses, damage mitochondrial function, and consequently disrupt the homeostasis of the organelle’s biochemical processes by increasing reactive oxidative species. Increased oxidative stress sets off a cascade of molecular events, disrupting optimal mitochondrial morphology and homeostasis. Furthermore, smoking-induced oxidative stress may also amalgamate with other health factors to contribute to various pathophysiological processes. An increasing number of studies show that toxins may affect mitochondria even through exposure to secondhand or thirdhand smoke. This review assesses the impact of toxins present in tobacco smoke and e-vapor on mitochondrial health, networking, and critical structural processes, including mitochondria fission, fusion, hyper-fusion, fragmentation, and mitophagy. The efforts are focused on discussing current evidence linking toxins present in first, second, and thirdhand smoke to mitochondrial dysfunction. Full article
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17 pages, 2023 KiB  
Article
Long-Term Dynamic Changes of NMDA Receptors Following an Excitotoxic Challenge
by Alberto Granzotto, Marco d’Aurora, Manuela Bomba, Valentina Gatta, Marco Onofrj and Stefano L. Sensi
Cells 2022, 11(5), 911; https://doi.org/10.3390/cells11050911 - 07 Mar 2022
Cited by 4 | Viewed by 1908
Abstract
Excitotoxicity is a form of neuronal death characterized by the sustained activation of N-methyl-D-aspartate receptors (NMDARs) triggered by the excitatory neurotransmitter glutamate. NADPH-diaphorase neurons (also known as nNOS (+) neurons) are a subpopulation of aspiny interneurons, largely spared following excitotoxic challenges. Unlike nNOS [...] Read more.
Excitotoxicity is a form of neuronal death characterized by the sustained activation of N-methyl-D-aspartate receptors (NMDARs) triggered by the excitatory neurotransmitter glutamate. NADPH-diaphorase neurons (also known as nNOS (+) neurons) are a subpopulation of aspiny interneurons, largely spared following excitotoxic challenges. Unlike nNOS (−) cells, nNOS (+) neurons fail to generate reactive oxygen species in response to NMDAR activation, a critical divergent step in the excitotoxic cascade. However, additional mechanisms underlying the reduced vulnerability of nNOS (+) neurons to NMDAR-driven neuronal death have not been explored. Using functional, genetic, and molecular analysis in striatal cultures, we indicate that nNOS (+) neurons possess distinct NMDAR properties. These specific features are primarily driven by the peculiar redox milieu of this subpopulation. In addition, we found that nNOS (+) neurons exposed to a pharmacological maneuver set to mimic chronic excitotoxicity alter their responses to NMDAR-mediated challenges. These findings suggest the presence of mechanisms providing long-term dynamic regulation of NMDARs that can have critical implications in neurotoxic settings. Full article
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17 pages, 3814 KiB  
Article
Impact of β-Amyloids Induced Disruption of Ca2+ Homeostasis in a Simple Model of Neuronal Activity
by Francisco Prista von Bonhorst, David Gall and Geneviève Dupont
Cells 2022, 11(4), 615; https://doi.org/10.3390/cells11040615 - 10 Feb 2022
Cited by 3 | Viewed by 1788
Abstract
Alzheimer’s disease is characterized by a marked dysregulation of intracellular Ca2+ homeostasis. In particular, toxic β-amyloids (Aβ) perturb the activities of numerous Ca2+ transporters or channels. Because of the tight coupling between Ca2+ dynamics and the membrane electrical activity, such [...] Read more.
Alzheimer’s disease is characterized by a marked dysregulation of intracellular Ca2+ homeostasis. In particular, toxic β-amyloids (Aβ) perturb the activities of numerous Ca2+ transporters or channels. Because of the tight coupling between Ca2+ dynamics and the membrane electrical activity, such perturbations are also expected to affect neuronal excitability. We used mathematical modeling to systematically investigate the effects of changing the activities of the various targets of Aβ peptides reported in the literature on calcium dynamics and neuronal excitability. We found that the evolution of Ca2+ concentration just below the plasma membrane is regulated by the exchanges with the extracellular medium, and is practically independent from the Ca2+ exchanges with the endoplasmic reticulum. Thus, disruptions of Ca2+ homeostasis interfering with signaling do not affect the electrical properties of the neurons at the single cell level. In contrast, the model predicts that by affecting the activities of L-type Ca2+ channels or Ca2+-activated K+ channels, Aβ peptides promote neuronal hyperexcitability. On the contrary, they induce hypo-excitability when acting on the plasma membrane Ca2+ ATPases. Finally, the presence of pores of amyloids in the plasma membrane can induce hypo- or hyperexcitability, depending on the conditions. These modeling conclusions should help with analyzing experimental observations in which Aβ peptides interfere at several levels with Ca2+ signaling and neuronal activity. Full article
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