Hyunsu Jung
Su Yeon Kim
Fatma Sema Canbakis Cecen
Yongcheol Cho
Seok-Kyu Kwon- 1Center for Functional Connectomics, Brain Science Institute, Korea Institute of Science and Technology, Seoul, South Korea
- 2Division of Life Sciences, Korea University, Seoul, South Korea
- 3Department of Biomedical Sciences, College of Medicine, Korea University, Seoul, South Korea
- 4Division of Bio-Medical Science & Technology, KIST School, Korea University of Science and Technology (UST), Seoul, South Korea
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.
Introduction
Mitochondria affect cellular functions via their roles in ATP production, lipid synthesis, reactive oxygen species (ROS) generation, and Ca2+ regulation. Recent studies of mitochondria-dependent Ca2+ handling have revealed the molecular identities of Ca2+-control components, including the mitochondrial calcium uniporter (MCU) and its auxiliary subunits (Mammucari et al., 2017). Furthermore, the development of enhanced Ca2+ sensors has enabled subcellular investigations of how mitochondria contribute to synaptic transmission. In addition, mitochondrial matrix-targeting sequence-tagged genetically encoded calcium indicators (GECIs) have allowed direct monitoring of mitochondrial Ca2+ dynamics (Kwon et al., 2016a).
In aged animals and humans, mitochondrial functional impairment is a key hallmark of brain aging (Grimm and Eckert, 2017; Mattson and Arumugam, 2018; Muller et al., 2018). Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and other aging-related neurodegenerative diseases also show mitochondrial defects. However, the detailed molecular mechanisms underlying these defects, particularly those related to mitochondrial Ca2+, have not yet been studied in depth.
Here, we describe mitochondrial Ca2+-related features and unveiled mitochondrial Ca2+ regulatory molecular mechanisms of brain aging and neurodegenerative disease models, and discuss experimental methods and controversies within the current research.
Mitochondrial Ca2+ Regulatory Components and Their Physiological Roles in Neurons
Ca2+ ions enter neurons through ionotropic glutamate receptors and voltage-dependent Ca2+ channels, with the imported Ca2+ then affecting various cellular processes, including the modulation of synaptic strength and Ca2+-mediated cell death (Ghosh and Greenberg, 1995). At the presynapse, Ca2+ triggers synaptic vesicle exocytosis, and residual Ca2+ alters synaptic release properties toward asynchronous release. Moreover, short-term synaptic plasticity can be controlled by presynaptic Ca2+ dynamics, while in dendrites, Ca2+ influences various signaling cascades involved in long-term synaptic plasticity and gene transcription (Hayashi and Majewska, 2005; Higley and Sabatini, 2008; Sudhof, 2012; Kaeser and Regehr, 2014; Kwon et al., 2016a).
Cytosolic Ca2+ is controlled by plasma membrane Ca2+ pumps and intracellular organelles, including mitochondria and the endoplasmic reticulum (ER). The ER imports Ca2+ through sarco/endoplasmic Ca2+ ATPase and releases it via ryanodine receptors or IP3 receptors (IP3Rs) (Verkhratsky, 2005). ER is partially tethered to mitochondria by mitochondria-associated membrane (MAM) or mitochondria-ER contact sites (MERCs) proteins such as Mitofusin 2, Sigma-1 receptor, vesicle-associated membrane protein-associated protein B (VAPB)/protein tyrosine phosphatase-interacting protein 51 (PTPIP51), IP3R/glucose-regulated protein (Grp75)/Voltage-dependent anion-selective channel 1 (VDAC1), and PDZ domain containing 8 (PDZD8), enabling ER-to-mitochondria Ca2+ transfer (Rapizzi et al., 2002; Szabadkai et al., 2006; Hayashi and Su, 2007; De Vos et al., 2012; Hirabayashi et al., 2017). The involvement of MAM in neurodegenerative diseases is a major topic in the field, but previous reviews wonderfully covered this scope (Paillusson et al., 2016; Liu and Zhu, 2017; Area-Gomez et al., 2018; Bernard-Marissal et al., 2018; Gomez-Suaga et al., 2018; Lau et al., 2018). Therefore, only a part of studies using direct observation of mitochondrial Ca2+ dynamics will be discussed here.
Several Ca2+ regulatory proteins have been identified in the outer and inner mitochondrial membranes. VDACs located in the outer mitochondrial membrane (OMM) are responsible for importing various ions and metabolites (Colombini, 2016). In the inner mitochondrial membrane, MCU mediates mitochondrial membrane potential-dependent Ca2+ influx into the mitochondrial matrix (Kirichok et al., 2004; Baughman et al., 2011; De Stefani et al., 2011). Reduced MCU-dependent Ca2+ uptake at presynaptic sites elevates cytosolic Ca2+ and alters short-term synaptic plasticity and synchronous release (Kang et al., 2008; Kwon et al., 2016b). In addition, a recent study showed upregulation of mitochondrial fission and dendritic mitochondrial Ca2+ transients following chemically induced long-term potentiation (LTP), with the interference of fission impairing mitochondrial Ca2+ uptake and LTP (Divakaruni et al., 2018).
Mitochondrial calcium uniporter forms complexes with other proteins, which regulate its opening dynamics (Mammucari et al., 2017; Pallafacchina et al., 2018). Mitochondrial calcium uptake protein 1/2/3 (MICU1/2/3) are the first MCU binding proteins to be characterized. MICU1 and MICU2 serve as molecular gatekeepers that negatively regulate MCU under low Ca2+ but positively regulate it under high cytosolic Ca2+ (Csordas et al., 2013; Patron et al., 2014; Liu et al., 2016). MICU3 is abundant in the brain and enhances mitochondrial Ca2+ uptake, with silencing of MICU3 in cortical neurons causing a reduction in stimulation-induced mitochondrial Ca2+ levels (Patron et al., 2019). Furthermore, the presynaptic MICU3-dependent increase in Ca2+ sensitivity allows MCU to open without Ca2+ release from ER and facilitates Ca2+-mediated mitochondrial ATP production and synaptic vesicle endocytosis (Ashrafi et al., 2020).
Essential MCU regulator (EMRE) is another MCU complex protein that bridges MCU and MICU1 and regulates the level of Ca2+ in the mitochondrial matrix. In addition, recent unveiled structural features of EMRE show that it triggers dimerization of MCU-EMRE complex and controls pore opening (Sancak et al., 2013; Vais et al., 2016; Wang et al., 2019). The MCU paralog MCUb exerts an inhibitory effect on MCU, with overexpression of MCUb completely abolishing MCU currents (Raffaello et al., 2013; Mammucari et al., 2017). Mitochondrial calcium uniporter regulator 1 (MCUR1) is a scaffold factor, whose absence results in the failure of MCU to form a complex (Tomar et al., 2016; Supplementary Figure 1).
The mitochondrial Na+/Ca2+ exchanger (NCLX) is one of the primary Ca2+ efflux units in mitochondria (Palty et al., 2010). Genetic ablation of NCLX increases Ca2+ retention in mitochondria and causes mitochondria-dependent cell death (Luongo et al., 2017). Also, H+/Ca2+ exchanger is considered as a Ca2+ efflux component, although its molecular identity is arguable (Jiang et al., 2009; De Marchi et al., 2014). Additional Ca2+ release-associated protein, mitochondrial permeability transition pore (mPTP), is activated by Ca2+ overload and ROS, leading to apoptosis or necrosis (Giorgi et al., 2018). This pore has been mainly studied under pathological conditions, including aging and neurodegenerative diseases, and the roles of core components including ATP synthase, cyclophilin D (CyPD), and the adenine nucleotide translocators (ANTs), are recently updated, although there are debates (Kokoszka et al., 2004; Bonora et al., 2013; Alavian et al., 2014; Karch and Molkentin, 2014; Raffaello et al., 2016; He et al., 2017; Rottenberg and Hoek, 2017; Zhou et al., 2017; Bernardi, 2018; Muller et al., 2018; Carroll et al., 2019; Karch et al., 2019).
Mitochondrial Ca2+ Dyshomeostasis in Aged Brains
Dysregulation of Ca2+ homeostasis is one of the hallmarks of brain aging (Mattson and Arumugam, 2018), with impaired Ca2+ control in aged brains resulting in various cellular and physiological deficits. Hippocampal CA1 pyramidal neurons in aged animals show elevated Ca2+ currents, as confirmed by Ca2+ imaging using multiple Ca2+ fluorophores (Landfield and Pitler, 1984; Disterhoft et al., 1996; Verkhratsky et al., 1998; Thibault et al., 2001; Lessmann et al., 2003). Age-associated Ca2+ changes have also been observed in other brain regions and in peripheral nerves (Verkhratsky et al., 1998).
Age-dependent dysregulation of Ca2+ results from various molecular changes, including increased voltage-gated Ca2+ channel expression, reduced Ca2+ binding protein expression, and impaired mitochondrial and ER Ca2+ handling (Mattson and Arumugam, 2018). Ca2+ isotope uptake by isolated synaptosomal mitochondria is significantly reduced in aged rat brains (Leslie et al., 1985). In addition, cytosolic Ca2+ dynamics in aged rodent brain slices or acutely dissociated neurons have been monitored using chemical Ca2+ dyes, such as Fura-2. Use of this dye in combination with a mitochondrial membrane potential indicator or mitochondrial uncoupler has revealed that the potential is disrupted in aged neurons, resulting in a decrease in mitochondrial Ca2+ uptake and an elevation of cytosolic Ca2+ upon stimulation (Xiong et al., 2002; Murchison et al., 2004). Mitochondrial Ca2+ buffering is also reduced in aged Rhesus monkeys, shown using isolated putamen mitochondria (Pandya et al., 2015).
Altered Mitochondrial Ca2+ Dynamics in AD
Ca2+ dysregulation is a common feature of several neurodegenerative diseases, including AD and PD (Beal, 1998; Zundorf and Reiser, 2011; Liao et al., 2017; Pchitskaya et al., 2018). Disruption of Ca2+ homeostasis and mitochondrial Ca2+ overload have been observed before pathological features of these diseases appear, highlighting the importance of neuronal Ca2+ regulation (Lesne et al., 2008; Surmeier et al., 2017).
AD is characterized by the accumulation of amyloid beta (Aβ) peptide, which is produced by abnormal proteolytic cleavage of amyloid precursor protein (APP), as well as by the formation of neurofibrillary tangles composed of tau protein and by neuronal loss, leading to learning and memory impairment (Oddo et al., 2003; Mattson et al., 2008). Mutations in APP or in the γ-secretase components presenilin1 and 2 (PSEN1/2) are the most well-characterized alterations contributing to dominantly inherited familial AD (FAD) (Chen et al., 2017; Muller et al., 2018).
Increased Aβ expression in FAD models or exogenous application of Aβ leads to elevated cytosolic Ca2+. In the past two decades, multiple underlying mechanisms have been suggested, including mitochondrial Ca2+ dysregulation (Du et al., 2008; Supnet and Bezprozvanny, 2010; Jadiya et al., 2019; Calvo-Rodriguez et al., 2020). In-vivo Ca2+ imaging with mitochondria-targeted Förster resonance energy transfer (FRET)-based GECI has directly demonstrated an Aβ-dependent mitochondrial Ca2+ increase in mouse cortex. This upregulation was observed prior to neuronal death, with blockade of MCU restoring the mitochondrial Ca2+ level in the APP/PS1 mutant mouse model (Calvo-Rodriguez et al., 2020).
Brain levels of NCLX protein are significantly reduced in human AD patients and in 3xTg-AD triple mutant mice (expressing mutations in APP, presenilin 1, and tau). Mutant APP-expressing-N2a cells also show decreased NCLX expression, resulting in impaired mitochondrial Ca2+ extrusion, consistent with the increased mitochondrial Ca2+ transients revealed by the mitochondria-localized GECI mito-R-GECO1. Alleviation of mitochondrial Ca2+ overload by NCLX expression in 3xTg-AD mice rescues cognitive decline and AD-related pathology (Jadiya et al., 2019). Another Ca2+ extrusion-related molecule, CypD, which is part of mPTP, is known to interact with mitochondrially transported Aβ. Inhibition or genetic ablation of CypD protects neurons from Aβ-triggered cell death and rescues impaired LTP and deficits in spatial learning and memory (Du et al., 2008).
Mitochondrial Ca2+ overload in AD can also result from impaired ER–mitochondria communication. Previous studies suggest that ER–mitochondria contacts are increased in AD models, promoting Ca2+ transfer to mitochondria (Zampese et al., 2011; Area-Gomez et al., 2012; Hedskog et al., 2013; Calvo-Rodriguez et al., 2019). ER-to-mitochondria Ca2+ transfer has been monitored using the mitochondria-localized chemical dye Rhod-5N or a mitochondrial matrix- or OMM-targeted protein Ca2+ sensors (Zampese et al., 2011; Hedskog et al., 2013; Calvo-Rodriguez et al., 2019). Opposite to these, some studies using electron microscopy (EM) and fluorescent imaging have reported reduced ER-mitochondria contacts in AD animal models and patients (Sepulveda-Falla et al., 2014; Martino Adami et al., 2019; Lau et al., 2020; Figure 1).
Figure 1. Neurodegenerative disease-related ER and mitochondrial proteins. AD, Alzheimer’s disease; PD, Parkinson’s disease; HD, Huntington’s disease; ALS, amyotrophic lateral sclerosis.
Apolipoprotein E4 (ApoE4) is the major risk factor for sporadic AD and it can increase ER–mitochondria contacts (Tambini et al., 2016; Orr et al., 2019). ApoE4-expressing cells show higher cytosolic and mitochondrial Ca2+, and given that ApoE4 expression alters neuronal MAM-tethering protein composition, this could explain enhanced MAM activity in sporadic AD (Orr et al., 2019; Table 1).
Table 1. Ca2+ dynamics in neurodegenerative disease models.
Furthermore, mitochondria contribute to the presynaptic defects observed in AD. Increased insulin-like growth factor-1 receptor (IGF-1R) levels are found in AD patient and mouse model brain samples (Moloney et al., 2010; Zhang et al., 2013). IGF-1R regulates synaptic transmission by modulating presynaptic mitochondrial Ca2+ buffering and ATP production, as measured using the mitochondria-targeted GECI and the ATP sensor, although detailed mechanisms are not known. Interestingly, inhibition of IGF-1R reverses altered synaptic release in an APP/PS1 mutant model (Gazit et al., 2016).
PD-Related Mitochondrial Ca2+ Dysfunction
Parkinson’s disease is characterized at the cellular level by dopaminergic neuron loss in the substantia nigra. Several genes contributing to PD pathogenesis have been identified, including α-synuclein, leucine-rich repeat kinase 2 (LRRK2), PTEN-induced kinase 1 (PINK1), and parkin (Abou-Sleiman et al., 2006; Ferreira and Massano, 2017). Ca2+ regulation is especially important for dopaminergic neurons because of their steady and autonomous pacemaker function (Chan et al., 2007; Guzman et al., 2010).
Mutation of α-synuclein and its aggregation into Lewy bodies are well-known pathological processes in PD. Interestingly, α-synuclein is localized to ER, mitochondria, and MAM and contributes to regulating ER–mitochondria communication (Li et al., 2007; Cali et al., 2012; Guardia-Laguarta et al., 2014). In one study, overexpression of WT or mutant α-synuclein in HeLa and SH-SY5Y cells was found to increase mitochondrial Ca2+ by enhancing ER–mitochondria interaction (Cali et al., 2012, 2019). However, another study using mutant α-synuclein-overexpressing cells produced conflicting results in terms of ER–mitochondria interactions (Guardia-Laguarta et al., 2014). Furthermore, overexpression of α-synuclein (WT/mutant) in SH-SY5Y cells disturbed the interaction between VAPB and PTPIP51, and this was accompanied by reduced ER-to-mitochondria Ca2+ transfer (Paillusson et al., 2017). High dose of WT/mutant α-synuclein can form the aggregates, and this in turn reduces ER-mitochondria contacts (Cali et al., 2012, 2019). Therefore, the dose-dependent effect could be the possible cause of discrepancies (Figure 1).
PINK1, a mitochondrial serine/threonine kinase, and parkin, an E3 ubiquitin ligase, are proposed to underlie mitochondrial quality control, with mutations in either gene highly related to PD (Narendra and Youle, 2011; Pickrell and Youle, 2015). Dopaminergic neuron-specific mitochondrial Ca2+ imaging with mito-GCaMP, a mitochondria-targeted GECI, in Drosophila PD models revealed elevated mitochondrial Ca2+. Pharmacological and genetic inhibition of IP3R and MCU restore mitochondrial Ca2+ and dopaminergic neuron loss (Lee et al., 2018). In contrast, due to negative regulation of NCLX, PINK1-deficient cortical neurons show reduced mitochondrial Ca2+ capacity and higher mitochondrial Ca2+ accumulation (Gandhi et al., 2009). Similarly, purified mitochondria from PINK1–/– mouse brain show a significantly decreased mitochondrial Ca2+ buffering capacity (Akundi et al., 2011).
Primary fibroblasts from PD patients with parkin mutations had reduced mitochondrial Ca2+ uptake due to loosened ER–mitochondria connectivity (Basso et al., 2018). Contrary to these results, other studies found that fibroblasts from Parkin-deficient mice or from PD patients with a parkin mutation show increased ER–mitochondria contacts (Gautier et al., 2016). In addition, OMM- and matrix-targeted Ca2+ sensors revealed higher ER-mitochondrial Ca2+ transfer (Gautier et al., 2016).
Dendrite shortening in LRRK2 mutant models is a well-known change related to mitochondrial dysfunction (Cherra et al., 2013). Abnormal mitochondrial function results from the stimulation-induced increase in mitochondrial Ca2+, which is accompanied by upregulated MCU expression. Interestingly, chemical inhibition or knockdown of MCU successfully restores neurite length (Verma et al., 2017; Table 1).
Dysregulation of Mitochondrial Ca2+ in Other Neurodegenerative Diseases
HD is a hereditary neurodegenerative disease characterized by involuntary movements, psychiatric abnormalities, and dementia. The major pathogenic features of the disease are progressive striatal neuronal loss, particularly of GABAergic medium spiny neurons, and extension of the N-terminal polyglutamine (polyQ) stretch of the huntingtin protein (Walker, 2007; Brustovetsky, 2016).
In the mutant huntingtin transgenic mouse brain, polyQ-stretched huntingtin is associated with the mitochondrial membrane (Choo et al., 2004). Interestingly, deficits in mitochondrial Ca2+ buffering have been observed after applying Calcium Green-5N to isolated mitochondria from HD mouse brain to monitor extramitochondrial Ca2+ (Panov et al., 2002). Live imaging of HD model striatal cell lines with mitochondria-targeted aequorin or Rhod-2AM indicates that mitochondria are able to handle a low Ca2+ challenge, but that a higher Ca2+ concentration disrupts their buffering ability (Lim et al., 2008; Quintanilla et al., 2013).
However, other studies demonstrated increased Ca2+ uptake capacity in isolated mitochondria from HD model mouse forebrains (Oliveira et al., 2007; Pellman et al., 2015). Furthermore, mitochondrial Ca2+ influx is higher in primary medium spiny neurons of HD model mice (Tang et al., 2005) and in fibroblasts from HD patients (Wang et al., 2013), which leads to cell death or mitochondrial DNA damage. Interestingly, this excitotoxicity is prevented by MCU or mPTP inhibition (Tang et al., 2005; Figure 1 and Table 1).
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive muscle paralysis resulting from the degeneration of upper and lower motor neurons. ALS exhibits multiple pathogenic features, including oxidative stress, mitochondrial dysfunction, and protein dysfunction of 43-kDa transactivating response region binding protein (TDP-43) and cytoplasmic Cu2+/Zn2+-superoxide dismutase 1 (SOD1) (Ferraiuolo et al., 2011; Lee et al., 2011; Tadic et al., 2014).
Monitoring with mitochondria-/ER-targeted ratiometric sensor proteins and Fura-2 identified elevated levels of mitochondrial, ER, and cytosolic Ca2+ in the motor neurons of ALS mutant transgenic mice (SOD1G93A) (Tradewell et al., 2011). However, in another study, Rhod-2- and Fura-2-based Ca2+ imaging showed significantly decreased mitochondrial Ca2+ uptake and increased cytosolic Ca2+ in SOD1G93A mice motor neurons (Kruman et al., 1999). Decreased mitochondrial Ca2+ buffering capacity in SOD1G93A-expressing mice can be restored by CypD deletion, which regulates mPTP opening, suppressing cell death (Parone et al., 2013). Other ALS mutant (SOD1G37R-overexpressing) N2a cells also show significantly reduced mitochondrial Ca2+ uptake and elevated cytosolic Ca2+ (Coussee et al., 2011).
Multiple studies suggest that specific molecular processes underlie ALS progression, but their findings are contentious. Hypoglossal motor neurons of SOD1G93A-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).
Other ALS-associated genes have also been identified, including TDP-43, fused in sarcoma (FUS), VAPB, and expanded hexanucleotide repeats in intron 1 of the encoding chromosome 9 open reading frame 72 (C9ORF72). The OMM protein PTPIP51 is a known binding partner of the ER protein VAPB. VAPB–PTPIP51 interaction in mouse motor neurons is disrupted by overexpression of ALS mutant or wild-type TDP-43 and FUS, also leading to disruption of Ca2+ homeostasis in HEK293T cells (Stoica et al., 2014, 2016). ALS patient fibroblast-derived motor neurons with C9ORF72 and TDP-43 mutations show delayed clearance of cytosolic Ca2+, lower mitochondrial buffering capacity, and imbalance of MICU1 and MICU2 expression (Dafinca et al., 2020) (Figure 1 and Table 1).
Discussion
In summary, brain aging and neurodegenerative diseases involve mitochondria- and ER-mitochondria contact-related Ca2+ regulatory defects. These alterations have been revealed using various experimental methods, including electrophysiological recording and live imaging. However, large part of in-vitro studies for neurodegenerative diseases have performed using cell lines and patient-derived fibroblasts rather than neurons. In addition, Ca2+ signals were triggered by various chemicals, and most conditions are not neurophysiological (Table 1). Depending on tissues and brain regions, mitochondrial Ca2+ uptake capacity and regulatory components can be different (Markus et al., 2016; Vecellio Reane et al., 2016; Patron et al., 2019). Therefore, application of recently advanced genetically encoded Ca2+ sensors for specific organelles will provide more precise neuron type-specific data (Kwon et al., 2016a).
Finally, mitochondrial Ca2+ regulatory molecular mechanisms have recently been revealed, with some studies showing that the composition of the MCU complex can change during disease progress and differ between mutant types (Table 1). Thus, revealing the detailed pathophysiological mechanisms of mitochondrial defects at the molecular level could lead to novel therapeutic targets that are specific for particular mutations and disease stages.
Author Contributions
HJ, SYK, FC, and S-KK wrote the manuscript and created the figures and table. S-KK and YC provided guidance and edited the manuscript. All authors contributed to the article and approved the submitted version.
Funding
S-KK was supported by grants from the Brain Research Program and the Bio and Medical Technology Development Program of the National Research Foundation funded by the Korean Government (nos. NRF2017M3C7A1043838, NRF2019M3E5D2 A01063794, NRF2019M3F3A1A02072175, and NRF2020R1C1C1 006386), and the Korea Institute of Science and Technology Institutional Program (no. 2E30070). YC was supported by a Korea University Grant.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Acknowledgments
A draft of this manuscript was edited by the Doran Amos, Ph.D., and Julia Slone-Murphy, Ph.D., ELS, of NeuroEdit Ltd.
Supplementary Material
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fcell.2020.599792/full#supplementary-material
Supplementary Figure 1 | MCU complex machinery. When the cytosolic Ca2+ level is low, MICU1/MICU2 heterodimer keeps MCU as a closed-form, whereas in high Ca2+ concentration, their conformational change helps MCU allow Ca2+ influx toward mitochondrial matrix. Otherwise, MICU1/MICU3 heterodimer has less gatekeeping function than MICU1/MICU2 dimer, which leads to opening the MCU complex in lower Ca2+ condition.
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Keywords: mitochondria, calcium regulation, aging, neurodegenerative disease, synaptic regulation
Citation: Jung H, Kim SY, Canbakis Cecen FS, Cho Y and Kwon S-K (2020) Dysfunction of Mitochondrial Ca2+ Regulatory Machineries in Brain Aging and Neurodegenerative Diseases. Front. Cell Dev. Biol. 8:599792. doi: 10.3389/fcell.2020.599792
Received: 28 August 2020; Accepted: 06 November 2020;
Published: 18 December 2020.
Edited by:
Yuzuru Imai, Juntendo University, JapanCopyright © 2020 Jung, Kim, Canbakis Cecen, Cho and Kwon. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Seok-Kyu Kwon, skkwon@kist.re.kr
†These authors have contributed equally to this work