Investigation of mitochondrial calcium uniporter role in embryonic and adult motor neurons from G93AhSOD1 mice

Tadić, Vedrana; Adam, Adam; Goldhammer, Nadine; Lautenschlaeger, Janin; Oberstadt, Moritz; Malci, Ayse; Le, Thanh Van; Sengupta, Saikata; Stubendorff, Beatrice; Keiner, Silke; Witte, Otto W.; Großkreutz, Julian

doi:10.1016/j.neurobiolaging.2018.11.019

Cited by 10 publications

(8 citation statements)

References 50 publications

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“…Furthermore, in a study comparing disease progression between transgenic and non-transgenic animals, increased MCU expression was observed in embryonic SOD1 mutant motor neurons, while MCU downregulation was observed in adult presymptomatic and symptomatic SOD1 mutant animals. The authors suspect that this decrease of MCU is likely a compensatory response to early calcium dyshomeostasis [ 141 ]. However, as the number of mitochondria and the mitophagy were not directly studied, it is unknown whether the decrease in MCU expression could be explained by decreased mitochondrial content.…”

Section: Mitochondrial Calcium Dysregulation In Neurodegenerative Diseasesmentioning

confidence: 99%

Excitotoxicity, calcium and mitochondria: a triad in synaptic neurodegeneration

Verma

Lizama

Chu

2022

Transl Neurodegener

170

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Glutamate is the most commonly engaged neurotransmitter in the mammalian central nervous system, acting to mediate excitatory neurotransmission. However, high levels of glutamatergic input elicit excitotoxicity, contributing to neuronal cell death following acute brain injuries such as stroke and trauma. While excitotoxic cell death has also been implicated in some neurodegenerative disease models, the role of acute apoptotic cell death remains controversial in the setting of chronic neurodegeneration. Nevertheless, it is clear that excitatory synaptic dysregulation contributes to neurodegeneration, as evidenced by protective effects of partial N-methyl-D-aspartate receptor antagonists. Here, we review evidence for sublethal excitatory injuries in relation to neurodegeneration associated with Parkinson’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis and Huntington’s disease. In contrast to classic excitotoxicity, emerging evidence implicates dysregulation of mitochondrial calcium handling in excitatory post-synaptic neurodegeneration. We discuss mechanisms that regulate mitochondrial calcium uptake and release, the impact of LRRK2, PINK1, Parkin, beta-amyloid and glucocerebrosidase on mitochondrial calcium transporters, and the role of autophagic mitochondrial loss in axodendritic shrinkage. Finally, we discuss strategies for normalizing the flux of calcium into and out of the mitochondrial matrix, thereby preventing mitochondrial calcium toxicity and excitotoxic dendritic loss. While the mechanisms that underlie increased uptake or decreased release of mitochondrial calcium vary in different model systems, a common set of strategies to normalize mitochondrial calcium flux can prevent excitatory mitochondrial toxicity and may be neuroprotective in multiple disease contexts.

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Section: Mitochondrial Calcium Dysregulation In Neurodegenerative Diseasesmentioning

confidence: 99%

Excitotoxicity, calcium and mitochondria: a triad in synaptic neurodegeneration

Verma

Lizama

Chu

2022

Transl Neurodegener

170

View full text Add to dashboard Cite

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“…In any case, the drug was not able to reduce the growth of breast cancer in a murine orthotopic xenograft model when applied alone [ 76 ]. A further candidate to activate MCUC is kaempferol, a plant flavonoid, observed in a few studies to increase mitochondrial calcium uptake [ [77] , [78] , [79] ]. However, caution must be exerted and proof of direct channel activation would be welcome, especially since this agent inhibits other channels, e.g.…”

Section: Mitochondrial Ion Channels and Their Pharmacological Targeting By Small Moleculesmentioning

confidence: 99%

Targeting mitochondrial ion channels for cancer therapy

2021

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Pharmacological targeting of mitochondrial ion channels is emerging as a promising approach to eliminate cancer cells; as most of these channels are differentially expressed and/or regulated in cancer cells in comparison to healthy ones, this strategy may selectively eliminate the former. Perturbation of ion fluxes across the outer and inner membranes is linked to alterations of redox state, membrane potential and bioenergetic efficiency. This leads to indirect modulation of oxidative phosphorylation, which is/may be fundamental for both cancer and cancer stem cell survival. Furthermore, given the crucial contribution of mitochondria to intrinsic apoptosis, modulation of their ion channels leading to cytochrome c release may be of great advantage in case of resistance to drugs triggering apoptotic events upstream of the mitochondrial phase. In the present review, we give an overview of the known mitochondrial ion channels and of their modulators capable of killing cancer cells. In addition, we discuss state-of-the-art strategies using mitochondriotropic drugs or peptide-based approaches allowing a more efficient and selective targeting of mitochondrial ion channel-linked events.

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“…Hypoglossal motor neurons of SOD1 G93A -transgenic mice show upregulated MCU and MICU1 expression at the end stage of the disease (P115-140) (Fuchs et al, 2013). However, in symptomatic cervical spinal cord motor neurons, MCU level is significantly decreased (Tadic et al, 2019).…”

Section: Dysregulation Of Mitochondrial Ca 2+ In Other Neurodegenerative Diseasesmentioning

confidence: 99%

Dysfunction of Mitochondrial Ca2+ Regulatory Machineries in Brain Aging and Neurodegenerative Diseases

Jung

Kim

Cecen

et al. 2020

Front. Cell Dev. Biol.

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Calcium ions (Ca2+) play critical roles in neuronal processes, such as signaling pathway activation, transcriptional regulation, and synaptic transmission initiation. Therefore, the regulation of Ca2+ homeostasis is one of the most important processes underlying the basic cellular viability and function of the neuron. Multiple components, including intracellular organelles and plasma membrane Ca2+-ATPase, are involved in neuronal Ca2+ control, and recent studies have focused on investigating the roles of mitochondria in synaptic function. Numerous mitochondrial Ca2+ regulatory proteins have been identified in the past decade, with studies demonstrating the tissue- or cell-type-specific function of each component. The mitochondrial calcium uniporter and its binding subunits are major inner mitochondrial membrane proteins contributing to mitochondrial Ca2+ uptake, whereas the mitochondrial Na+/Ca2+ exchanger (NCLX) and mitochondrial permeability transition pore (mPTP) are well-studied proteins involved in Ca2+ extrusion. The level of cytosolic Ca2+ and the resulting characteristics of synaptic vesicle release properties are controlled via mitochondrial Ca2+ uptake and release at presynaptic sites, while in dendrites, mitochondrial Ca2+ regulation affects synaptic plasticity. During brain aging and the progress of neurodegenerative disease, mitochondrial Ca2+ mishandling has been observed using various techniques, including live imaging of Ca2+ dynamics. Furthermore, Ca2+ dysregulation not only disrupts synaptic transmission but also causes neuronal cell death. Therefore, understanding the detailed pathophysiological mechanisms affecting the recently discovered mitochondrial Ca2+ regulatory machineries will help to identify novel therapeutic targets. Here, we discuss current research into mitochondrial Ca2+ regulatory machineries and how mitochondrial Ca2+ dysregulation contributes to brain aging and neurodegenerative disease.

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Investigation of mitochondrial calcium uniporter role in embryonic and adult motor neurons from G93AhSOD1 mice

Cited by 10 publications

References 50 publications

Excitotoxicity, calcium and mitochondria: a triad in synaptic neurodegeneration

Excitotoxicity, calcium and mitochondria: a triad in synaptic neurodegeneration

Targeting mitochondrial ion channels for cancer therapy

Dysfunction of Mitochondrial Ca2+ Regulatory Machineries in Brain Aging and Neurodegenerative Diseases

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