fnins-14-589319

REVIEW
published: 09 November 2020

doi: 10.3389/fnins.2020.589319
MERCs. The Novel Assistant to

Neurotransmission?
Olesya M. Shirokova 1* , Pavel V. Pchelin 1,2 and Irina V. Mukhina 1,2
1
Central Scientific Research Laboratory, Institute of Fundamental Medicine, Privolzhsky Research Medical University, Nizhny
Novgorod, Russia, 2 Department of Neurotechnology, Institute of Biology and Biomedicine, Lobachevsky State University of
Nizhny Novgorod, Nizhny Novgorod, Russia
In neuroscience, much attention is paid to intercellular interactions, in particular, to

synapses. However, many researchers do not pay due attention to the contribution
of intracellular contacts to the work of intercellular interactions. Nevertheless, along
with synapses, intracellular contacts also have complex organization and a tremendous
number of regulatory elements. Mitochondria-endoplasmic reticulum contacts (MERCs)
are a specific site of interaction between the two organelles; they provide a basis for
a large number of cellular functions, such as calcium homeostasis, lipid metabolism,
autophagy, and apoptosis. Despite the presence of these contacts in various parts of
neurons and glial cells, it is yet not known whether they fulfill the same functions. There
are still many unsolved questions about the work of these intracellular contacts, and
Edited by:
Shun-Fen Tzeng, one of the most important among them is if MERCs, with their broad implication into
National Cheng Kung University, synaptic events, can be considered the assistant to neurotransmission?
Taiwan
Keywords: synapse, endoplasmic reticulum, mitochondria-endoplasmic reticulum contacts, calcium
Reviewed by:
homeostasis, neurodegenerative diseases, synaptic transmission
Seok-Kyu Kwon,
Korea Institute of Science
and Technology (KIST), South Korea
Chih-Yen Wang, INTRODUCTION
Baylor College of Medicine,
United States Synaptic transmission is a complex process of communication between neuronal and target cells
*Correspondence:
(Meriney and Fanselow, 2019). Many membrane structures and organelles are involved in synaptic
Olesya M. Shirokova transmission, including the synaptic plasma membrane and receptors, synaptic vesicles, structures
[email protected] in synaptic spines, mitochondria, endoplasmic reticulum (ER), and autophagosomes (Vos et al.,
2010; Liang, 2019). Over the last decade it became evident that due to their typical elongated
Specialty section: structure, mitochondria and the ER can form contacts with other organelles, thus modulating
This article was submitted to a broad spectrum of intracellular processes (Bravo-Sagua et al., 2014). Studies demonstrate the
Neurodegeneration, existence of a physical and functional connection between the ER and mitochondria via the
a section of the journal
junctions called mitochondria-endoplasmic contacts (MERCs) or, in case of an isolated fraction
Frontiers in Neuroscience
of these contacts, mitochondria-associated membranes (MAM) (Giorgi et al., 2015). MAMs are a
Received: 30 July 2020
product of the biochemical enrichment of mitochondria and ER membranes linked to each other
Accepted: 19 October 2020
and include many proteins and lipids that form MERCs (Janikiewicz et al., 2018). As well as in
Published: 09 November 2020
non-neuronal cells, MERCs were characterized in cells across the central nervous system, mostly
Citation:
in neurons (Gómez-Suaga et al., 2019), while, in astrocytes (Goebel et al., 2019), the data are
Shirokova OM, Pchelin PV and
Mukhina IV (2020) MERCs. The Novel
scarce, and there is only indirect evidence of MERCs’ presence in microglia (Xie et al., 2017), and
Assistant to Neurotransmission? oligodendrocytes (Simpson et al., 1997). Due to their distribution and carried out functions, it is
Front. Neurosci. 14:589319. brought into question whether MERCs can play a significant role in synaptic transmission and serve
doi: 10.3389/fnins.2020.589319 as an important link connecting mechanisms in the pathogenesis of neurodegenerative diseases,
Frontiers in Neuroscience | www.frontiersin.org 1 November 2020 | Volume 14 | Article 589319

Shirokova et al. MERCs, Novel Assistant to Neurotransmission?
thus serving as a promising therapeutic target. Still, among to each other. Similarly, MERCs with the 30 nm cleft can be
all membrane structures potentially involved in supporting either Ca2+ -MERCs or inactive phagocytic MERCs. Thus, the
neurotransmission, the complex of MERCs remains to be dynamics of the contact structure will play a key role in regulating
the least studied. MERCs activity, despite the complex distribution of various types
Consequently, the purpose of this review is to designate the of mitochondria-ER contacts. At present, it is not yet clear,
possible role of MERCs in supporting active neurotransmission whether there is a single mechanism that regulates the dynamics
under normal conditions and to outline how altered MERCs of all mitochondria-ER contacts, or if MERCs have different
function can contribute to the development of failing organization initially (Giacomello and Pellegrini, 2016).
neurotransmission in neurodegenerative diseases. The question Another important structural characteristic of MERCs is their
brought to the discussion is whether MERCs could be considered length. Despite the fact that the MAM proteome is rather
an important assistant to neurotransmission. conservative in various cell types (Wang X. et al., 2018), the
length of mitochondria-ER contacts may differ depending on the
specific cell type (Giacomello and Pellegrini, 2016). For example,
MERCs STRUCTURE AND FUNCTIONS in mouse fibroblast cell cultures, 2.25% of the mitochondrial
IN NEURONAL CELLS membrane is in close contact (<20 nm) with the ER (Cosson
et al., 2012), in HeLa cells – 5–20% (Rizzuto et al., 1998), about 7%
Structure in neuronal cultures (Martino Adami et al., 2019), and about 10%
Even though MERCs are shown to be present in multiple parts of in lymphoma cells (Csordás et al., 2006). Researchers observed
the neuron (Lee et al., 2018), the precise characteristics of these the ER completely covering the mitochondrion around the area
contact sites remain to be under discussion. of its division (Friedman et al., 2011). Even though the molecular
In general, MERCs comprise a set of chemical bonds, many of pathways implicated in the change of MERCs length are not
which are found both in the ER and mitochondria. Other proteins yet elucidated, this property of MERCs changes in pathological
are localized to the membrane of only one organelle, but still conditions (Leal et al., 2016). For instance, under conditions of
are concentrated precisely at the contact site. The huge variety mutant α-synuclein expression, the decrease in MERCs length
of proteins (>1000), discovered during the fractionation (Poston leads to impaired Ca2+ homeostasis (Paillusson et al., 2017).
et al., 2013) of MAM, can be explained by the imperfection of The increased contact surface can lead to significant metabolic
techniques that cannot isolate the proteins only in the area of alterations (Bray, 2018). Such an increase was shown to elevate
interaction. However, it is considered that the main connecting mitochondrial Ca2+ content and ATP production promoting the
link of MERCs is the tripartite complex, which transports ions recovery of damaged axons (Lee et al., 2019).
of calcium (Ca2+ ) and is composed of inositol 1,4,5-triphosphate
receptor (IP3R) on the ER membrane [see (Serysheva, 2014) for Functions
more details on the channel structure], voltage-dependent anion During active synaptic transmission, it is crucial to supply the
channel 1 (VDAC1) on the outer membrane of mitochondria and synapse with a high enough level of energy (Harris et al., 2012),
the connecting cytosolic chaperone of glucose-regulated protein support the local Ca2+ balance, and provide the lipid synthesis
75 (GRP75; a member of the heat shock protein family, 70 kDa) to ensure the membrane fluidity, the renewal and modification
(Honrath et al., 2017). Among other MERCs functional protein of synaptic structures, such as vesicles, channels, and dendritic
complexes are mitofusin homo- and heterodimers (Mfn1-Mfn2) spines (Rodríguez-Berdini and Caputto, 2019). Since the main
(function: modulation of mitochondrial mobility, auto- and functions of MERCs include the influence on mitochondrial
mitophagy) (de Brito and Scorrano, 2008; Filadi et al., 2015), mobility and morphology (Tagaya and Arasaki, 2017; Giacomello
the complex of ER protein VAPB (vesicle-associated membrane et al., 2020), the exchange of calcium (Marchi et al., 2017; Müller
protein-associated protein B/C) and mitochondrial PTPIP51 et al., 2018; Cherubini et al., 2020) and lipids (Vance, 2014;
(protein tyrosine phosphatase-interacting protein 51) [function: Hanada, 2017) between organelles, and participation in processes
molecular scaffold between ER and mitochondria related to of autophagy (Hamasaki et al., 2013; Garofalo et al., 2016; Tagaya
Ca2+ -exchange (Liu and Zhu, 2017; Paillusson et al., 2017), and Arasaki, 2017), and apoptosis (Liu et al., 2014; Perkins and
autophagy (Gomez-Suaga et al., 2017)], the complex of ER Ellisman, 2016; Figure 1), these intracellular contacts, localized
chaperone protein BAP31 (B-cell receptor-associated protein 31) in neurons and astrocytes, appear to be an indispensable assistant
and mitochondrial fission protein FIS1 (Fission 1) (function: to neurotransmission.
transmission of apoptotic signals from mitochondria to ER) are
also distinguished among the functional complexes of MERCs Mitochondrial Fission and Mobility
(Iwasawa et al., 2011; Krols et al., 2016), as well as many other Mitochondrial transport and distribution are especially crucial
proteins (Raturi and Simmen, 2013). for neurons. Their specific structure with extended axons
Cleft width is one of the key characteristics that allow assessing and dendrites requires high energy consumption at significant
the status and functional role of MERCs. According to the distances from the cell’s body, in particular, in synapses (Palikaras
hypothesis, MERCs with 10 nm cleft width perform lipid transfer and Tavernarakis, 2020). For neurons to perform functions
between organelles, ≈20 nm cleft width change their function to such as integration and signal transmission, the presence of
Ca2+ exchange. Nevertheless, there are also “inactive” MERCs a sufficient number of functionally active mitochondria is
ready for activation as soon as two membranes get close enough necessary (Sheng, 2017).

FIGURE 1 | Main biochemical connections of MERCs (Mitochondria–endoplasmic reticulum contacts), their functions. ER-IP3R interacts with the mitochondrial
channel VDAC1 together with chaperone GRP75, the main function is calcium transport. ER-VAPB interacts with mitochondrial PTPIP51 to form the molecular
scaffold between ER and mitochondria related to Ca2+ -exchange. ER-resident protein BAP31 interacts with mitochondrial protein FIS1. Together with PACS-2, this
complex regulates the initiations of apoptosis. Mitofusin bridges (formed with Mfn1 and Mfn2) can be homodimers and heterodimers that change mitochondrial
dynamics: mobility, fusion, and fission.
Due to the presence of mitofusins (Mfn1, Mfn2) (Bernard- outer mitochondrial membrane (Honrath et al., 2017). The
Marissal et al., 2015) MERCs are involved in such physiological maintenance of this function was also shown to be supported by
processes as mitochondrial fission and mobility inside the the VAPB-PTPIP51 complex (Paillusson et al., 2017) and PDZD8
cell, auto- and mitophagy. However, the exact mechanism of protein (Hirabayashi et al., 2017).
mitofusins’ influence on the MERCs functioning and structure Disruption of calcium transmission and other stress factors
remains to be not fully understood (Filadi et al., 2015), and subsequently lead to the accumulation of proteins with impaired
was questioned by many authors (Cosson et al., 2012; Filadi structure, which triggers unfolded protein response (UPR), the
et al., 2015; Wang et al., 2015). Mfn−2 knockdown increases process mainly aimed to suppress the translation, to induce
the length of ER-mitochondria contacts without affecting their misfolded protein degradation, and to stimulate the formation
number (Leal et al., 2016). Recently, a direct correlation between of folding-related chaperones. However, if the cause cannot be
the form of mitochondria and the number/length of MERCs was eliminated, the UPR will initiate apoptosis. This is proved in
found (Nagashima et al., 2019), and it was speculated that this numerous experiments on the depletion of such MAM proteins
intracellular interaction is necessary to maintain the complex as Mfn2, SIGMA1R, and PACS-2 (phosphofurin acidic cluster
shape of mitochondria. sorting protein 2), as well as by the expression of the mutated
form of VAPB, all of which induced UPR (Simmen et al., 2005,
Calcium Homeostasis 2010; Langou et al., 2010; Muñoz et al., 2013; Prause et al., 2013;
It is widely known that Ca2+ is considered to be an Bernard-Marissal et al., 2015).
indispensable participant in mechanisms maintaining synaptic
plasticity (Mateos-Aparicio and Rodríguez-Moreno, 2020). In Lipid Homeostasis
cells, ER-mitochondria Ca2+ exchange is performed with MERCs Lipids constitute an integral part of synaptic transmission,
GRP75 protein, which promotes the opening of IP3R calcium providing the formation of new membrane structures such as
channels in the ER in the direct proximity to VDAC on the synaptic vesicles (Sudhof, 2004), modifying the function of ion

channels (Carta et al., 2014), and the signal propagation along morphology, and mitochondrial properties in synapses can
axons (Korinek et al., 2020). The functions of biochemical bonds vary significantly even between neurons within the same path
formed by MERCs include phospholipid remodeling, cholesterol (Hollenbeck, 2005). Further, we consider the role of MERCs
biosynthesis, phosphatidylserine synthesis. The intracellular in synapses, where mitochondria are present in the pre- or
conversion of free cholesterol creates a dynamic balance between postsynaptic parts. The characteristics of mitochondria-free
membrane-bound and cytoplasmic cholesterol. Even though synapses, which can carry out neurotransmission using glycolysis
the molecular mechanisms that regulate the dynamics of as the energy source (Jang et al., 2016; Ashrafi et al., 2017), are not
the association between mitochondria and the endoplasmic discussed in this review.
reticulum remain as of yet unknown (Nagashima et al., 2019), Most excitatory axons contact with dendritic spines, whereas
researchers (Fujimoto et al., 2012) found an increase in inhibitory axons establish contacts mainly directly with
the membrane association of these organelles, using methyl- dendrites. As is known, mitochondria are exceedingly rarely able
β-cyclodextrin (MβC) (removes cholesterol from membranes). to get into dendritic spines (Kasthuri et al., 2015). Therefore, it
Therefore, under normal conditions cholesterol fulfills a is most likely that MERCs do not directly influence all types of
restrictive role in the structural organization of MERCs synaptic contacts, or rather not influence equally. The data of
(Fujimoto et al., 2012). ultrastructural analysis confirm the presence of contacts between
the ER and mitochondria in different parts of neurons (Wu
Synaptic Autophagy et al., 2017; Hirabayashi et al., 2018) and astrocytes (Proulx and
Autophagy is known to regulate neurotransmission in the Borgmann, 2020). It is known that mitochondria in various
presynapse by the elimination of defective vesicles, and in parts of neurons are of different populations: in particular, in cell
the postsynapse by the disruption of structural proteins bodies and dendrites, these are complex mitochondrial networks,
(Lieberman and Sulzer, 2020). Even though the data are scarce while in axons discrete mitochondria are present (Popov et al.,
to date, it appears that MERCs are linked to autophagy 2005). Consequently, the functional role of MERCs in different
during synaptic transmission. Firstly, membrane lipids, which parts of neurons can vary significantly.
are synthesized and modified in MAM, are known to be At present, no in-depth study on the localization of MERCs
required for the formation of autophagosomes (Nagashima et al., and their characteristics within individual types of brain
2019). Secondly, a high level of autophagy is required during cells or in various parts of the central nervous system was
neuronal stimulation for synaptic plasticity (Glatigny et al., carried out. Different types of tissues, their specific metabolic
2019). Though it is worth mentioning that different forms state are characterized by a certain amount of intracellular
of autophagy may be present in a cell’s body and synapses contacts. Moreover, the number of MERCs changes during
(Vijayan and Verstreken, 2017). The precise mechanisms of the process of neurodegeneration (Leal et al., 2016) and aging
MERCs’ proteins involvement in synaptic autophagy are yet (Calvo-Rodríguez et al., 2016).
not known, however, the loss of MERCs and the disruption of
autophagosome formation were observed when the expression Presynaptic Support
of PACS-2 or Mfn-2 was reduced. On the contrary, VAPB Mitochondria in the axon exist in the form of two populations:
and PTPIP51 knockdown also led to the MERCs loss, but in mobile and stable. The high proximity of mitochondria
this case, autophagy was stimulated (Hamasaki et al., 2013; to synapses is necessary due to the high energy demands
Gomez-Suaga et al., 2017). during neurotransmission, therefore, there are mechanisms
Still, it is yet to be elucidated, whether functional and for mitochondrial retention near active synapses (Mironov
morphological types of MERCs have different biochemical bonds and Symonchuk, 2006). Thus, it is known that mitochondria
and interactions. It is quite likely that mitochondrial contacts during the functional work of synapses are the main sources
with a rough or smooth ER can form individual subdomains with of energy (Harris et al., 2012). Different studies demonstrate
unique specialized functions, and only a part of these functions is various numbers of axonal mitochondria near the synapse:
currently studied using standard sample preparation method. 36% (Chang et al., 2006) or 50% of axonal buds may contain
mitochondria (Lewis et al., 2016), since mitochondrial mobility
is regulated by mechanisms of the structural and functional
MERCs IN SYNAPTIC TRANSMISSION plasticity in axons and synapses (Cai et al., 2011). Notably,
one of the components of MERCs is Drp1 (Friedman et al.,
Synaptic contact, or synapse, represents an interaction between 2011), which indirectly influences neurotransmission. Drp1
two neurons in the central nervous system. Nevertheless, is involved in mitochondrial fission (Friedman et al., 2011),
according to the modern concept, the synapse consists of contributes to the formation of synaptic vesicles pool in
three main parts: presynaptic terminal, postsynaptic terminal, developing synapses (Li et al., 2008), participates in maintaining
and astrocyte process near the synaptic cleft (Perea et al., the bioenergetics of astroglial cells (Motori et al., 2013). As is
2009). MERCs are present in pre- and postsynaptic parts known, presynaptic mitochondria, which number is related to
(Gómez-Suaga et al., 2019), modulation of this connection in Drp1 activity, regulate a short-term increase in the release of
astrocytes changes their activity (Stephen et al., 2014), hence neurotransmitters during a period of frequent synaptic activity
MERCs appear to affect the whole synapse as well (Figure 2). (Jonas, 2006) and regulate vesicle replenishment (Verstreken
Individual synapses have different properties, physiology and et al., 2005). Drp1 mutations lead to impaired mitochondrial

FIGURE 2 | MERCs support synaptic activity in three sides: presynapse, postsynapse, and astrocyte. The implication of MERCs into supporting the active
neurotransmission is connected with changes in calcium and lipid homeostasis, mitochondrial dynamics in pre- and postsynapse, due to the effects of SIGMA1R
(shown as a blue star symbol) on ionic currents and membrane receptors. Dopamine D1 receptors – D1R, small conductance Ca2+ -activated potassium channels –
SK, NMDA-receptors – NMDAR.
dynamics and, as a result, to a lack of energy for synaptic synapse, except when under conditions of prolonged synaptic
neurotransmission during prolonged stimulation. Besides, the activity. Finally, a decrease in the axonal ER-calcium content
mobility of mitochondria affects local protein synthesis and leads to the activation of a temperature-dependent mechanism
hence the remodeling of synapses in general. However, that modulates the release of the neurotransmitter, and this
taking into account the exceptional role of mitochondria in process is completely dependent on STIM (calcium sensor –
synaptic transmission, to date, the reason for the absence Stromal interaction molecule), the integral protein of the ER
of mitochondria in some synapses remains to be unclear and plasma membranes. Since one of the functions of MERCs
(Devine and Kittler, 2018). is Ca2+ transfer from the ER to mitochondria through the
The endoplasmic reticulum is present along the axon (Wu tripartite protein complex, it appears to be possible to control
et al., 2017), allowing intracellular transport (Droz et al., 1975), the release of a neurotransmitter by targeting this intracellular
and the regulation of calcium kinetics (Luarte et al., 2018). contact (Yang et al., 2010).
The role of MERCs is crucial for the regulation of calcium A recent study highlights the role of membrane cholesterol
at the local subcellular level (Krols et al., 2016). A recent in synaptic transmission; in particular, in action potential
study (de Juan-Sanz et al., 2017) discussed the possibility of propagation along the axon, in the modulation of spontaneous
feedback between neuronal activity and the energy status of a release of glutamate at the presynapse, and the regulation of the
whole cell. The authors made several remarkable conclusions. opening and localization of NMDA receptors at the postsynapse
Firstly, the activity of neurons leads to the influx of Ca2+ to (Korinek et al., 2020). It was shown before that cholesterol
the axonal ER, not to the efflux. Secondly, axonal ER-calcium increases the number of vesicles present in the presynaptic
does not affect the cytosolic levels of Ca2+ in proximity to the terminal and the probability of their release, which leads to

the general stimulation of presynaptic function (Dason et al., Astrocytic Support

2014). It also appears evident that the transfer of cholesterol The third part of a synapse is the membrane of the glial
across MAM from the ER to the mitochondrial membrane is process, although not all synapses are associated with glial
necessary for steroidogenesis, correct organization of mtDNA, presence as their functional part, for instance, in the neocortex
and to provide the intramitochondrial antioxidant protection there is only 50% of such synaptic contacts (Kasthuri et al.,
(Arenas et al., 2017). The overall decrease in cholesterol leads 2015). Three-dimensional reconstruction proves the existence of
to its reduced amount in MAM, which alters autophagy, mitochondria-endoplasmic contacts in the processes of astrocytes
as well as membrane fluidity and, as a result, a change in (Goebel et al., 2019). However, when determining the role in
the ratio of amyloidogenic/non-amyloidogenic APP processing modulating the synaptic transmission of MERCs located in
(Arenas et al., 2017). the glial processes, not only should the percentage of synapses
with glial processes in their composition be taken into account
Postsynaptic Support but also the cellular, molecular and functional diversity of
In the postsynaptic part, at the level of dendrites or dendritic the astrocytes themselves in the adult brain (John Lin et al.,
spines, the effect of MERCs on synaptic transmission can be 2017). It remains not completely understood how intracellular
modulated in different ways. In axo-dendritic synapses, MERCs contacts differ in these subpopulations of astrocytes. Besides, the
are close to the terminals. In dendrites, the important role of activity of the synapses themselves also affects the morphology
ER-mitochondria tethering protein PDZD8 was demonstrated of the astrocytic processes (Morel et al., 2014). The importance
in supporting the local Ca2+ homeostasis (Hirabayashi et al., of the connection between MAM-associated proteins and glia
2017). On the contrary, a different situation is observed during synaptic transmission is proved by SIGMA1R or PACS-2
in axo-spine synapses, since mitochondria extremely rarely knockdown using siRNA in neuron-glial networks in vitro, which
enter the dendritic spines (von Bohlen Und Halbach, 2009), caused degeneration of processes in both neurons and astrocytes
but at the same time, the ER is found in many spines (Hedskog et al., 2013).
(Toresson and Grant, 2005). Mitochondria-endoplasmic reticulum contacts in astrocytes
It was demonstrated that such conservative MERCs proteins regulate mitochondrial mobility (Filadi et al., 2015).
as PSS1 (phosphatidylserine synthase-1), PACS-2, IP3R3, Mitochondria in astrocytic processes are mobile (Lovatt et al.,
SIGMA1R, Mfn2, and VDAC1 are ubiquitously localized to 2007; Lavialle et al., 2011) and linger in places of high synapse
these contact sites in the cell bodies, processes, and synapses activity, since there are a large number of glutamate transporters
of neurons (Hedskog et al., 2013). MERCs are involved in (Jackson et al., 2014). Moreover, the mobility of mitochondria
supporting the active neurotransmission with SIGMA1R is mediated by microtubules, but is mainly regulated by actin
protein. The decrease in the Ca2+ concentration in the ER filaments with a change in the concentration of cytosolic calcium
causes the dissociation of SIGMA1R from BiP (binding (Kremneva et al., 2013).
immunoglobulin protein), allowing the chaperone activity of As is known, several astrocytic functions are triggered
the receptor to be activated. Further, SIGMA1R stabilizes IP3R3 in dependence on certain concentrations of cytosolic Ca2+
to carry out Ca2+ exchange between organelles, supporting (Bernardinelli et al., 2014). Among these functions are the release
the bioenergetics of the cell (Hayashi et al., 2009). The IP3R- of gliotransmitters (Papouin et al., 2017; Sherwood et al., 2017),
VDAC complex, stabilized by SIGMA1R, is of particular rapid removal of neurotransmitters from the synaptic cleft (e.g.,
importance, since it is controlled from both organelles, notifying glutamate, which causes excitotoxicity in high concentrations),
about its condition (Goetz et al., 2007). According to the mitophagy of neuronal defective mitochondria, elimination of
modern concept (Kourrich et al., 2012), in the process of synapses (Allen and Eroglu, 2017). According to the recent
neurological disorders development, SIGMA1R is translocated data, astrocytes are capable of transferring new mitochondria
from MERCs to other parts of the cell, as a result of which to axons (Hayakawa et al., 2016). Also, astrocytes are thought
SIGMA1R binds to various ion channels, receptors, or kinases to be the most effective cholesterol synthesis sites in the brain
(NMDA, Src, D1R, PLC, DA transporter) and modulates their (Nieweg et al., 2009). Astrocytes affect the progenitor cells
activity. SIGMA1R translocation triggers many reactions of of oligodendrocytes, and, accordingly, their viability (Varela-
this receptor with various ion channels (Schmidt and Kruse, Echevarría et al., 2017). Since all of the mentioned functions are
2019). SIGMA1R-NMDAR interactions are related to learning directly or indirectly influenced by a certain Ca2+ content in the
and memory. The effect on the function of NMDAR occurs cytosol, the role of MERCs, as a site of Ca2+ transfer between
due to the direct modulation of small-conductance Ca2+ - organelles, is highly significant. Thus, an increase in the level of
activated potassium channels (Kourrich et al., 2012). SIGMA1R GRP78 (BiP) protein, which is involved in calcium transmission
is also capable of suppressing the functions of NMDAR, for between organelles, was used to protect mitochondria and
example, in retinal neurons, presumably via the PLC-PKC contributed to the survival of astrocytes in acute ischemia and
pathway, which depends on the Ca2+ concentration (Zhang other pathological conditions, which include mitochondrial and
et al., 2011). Free SIGMA1R exerts a significant influence ER dysfunctions (Ouyang et al., 2011).
on synaptic plasticity and the process of neurodegeneration. As alluded to above, one of the MERCs main functions is the
SIGMA1R is shown to stimulate BDNF-induced activation of maintenance of lipid homeostasis (Vance, 2014). In mice with
phospholipase C (PLC)-gamma and the release of glutamate reduced lipid synthesis, especially in astrocytes, there are also
(Gómez-Suaga et al., 2018). a reduced release of cholesterol from astrocytes and impaired

synaptic development with fewer amounts of presynaptic vesicles role of MERCs proteins concerning neuronal integrative
and defects in synaptic plasticity (van Deijk et al., 2017). properties (Hedskog et al., 2013). Therefore, MERCs proteins
MAM-associated enzymes provide the synthesis and transfer potentially could be used as molecular targets in creating a
of phospholipids, cholesterol, and ceramides. With cholesterol new neuroprotective approach. Taking that into account, the
depletion, the connection between two organelles increases link between MERCs functions and the pathogenesis of such
(Fujimoto et al., 2012). However, at present, the exact mechanism neurodegenerative pathologies as Alzheimer’s, Parkinson’s, and
by which cholesterol is transferred from the ER to mitochondrial Huntington’s diseases received much attention recently due to the
outer membranes was not determined, and the role of MAM novel observations (De Mario et al., 2017; Moltedo et al., 2019;
in this transport process requires further study, in particular, in Magalhães Rebelo et al., 2020).
astrocytes (Vance, 2014).
Reactive astrocyte activity following injury leads to the Alzheimer’s Disease
formation of glial scars, which prevent axonal growth, forming Pathogenesis of Alzheimer’s disease (AD) serves as a good
a physical and biochemical barrier (Chen et al., 2002; Varela- example of the emerging role of MERCs proteins in
Echevarría et al., 2017). However, overexpression of mitofusins supporting synaptic transmission during the development
(one of the MAM components) triggers apoptosis in astrocytes of neurodegeneration. The loss of synapses correlates with the
(Liu et al., 2014) and other cell types (Wang W. et al., 2018). Thus, cognitive impairment in patients with AD and is considered to be
MERCs can be considered to be a potential therapeutic target a preceding mechanism of neuronal loss in affected brain areas
to protect the nervous system from astrogliosis, which disrupts (Tönnies and Trushina, 2017). In general, AD is characterized by
the regeneration of processes and interferes with synaptic the β-amyloid (Aβ) plaque formation and the accumulation of
transmission (Liu et al., 2018). Overexpression of Mfn2 changes neurofibrillary tangles, which consist of hyperphosphorylated tau
the Bcl-2/Bax ratio (Wang W. et al., 2018). Bcl-2 regulates IP3R protein, in the brain. The amount of synapse-localized oligomeric
and, accordingly, storage of Ca2+ in the ER (García-Sáez, 2012), Aβ correlates with excitatory synapse loss (Koffie et al., 2009). It is
Mfn2 can activate Bax and inhibit Bcl-2 expression. Thus, Mfn2 important to note that the oligomeric form of Aβ is considered to
triggers the inhibition of the anti-apoptotic protein and the be the most synaptotoxic (Kayed and Lasagna-Reeves, 2013). The
activation of the proapoptotic protein. precursor of Aβ is the transmembrane protein APP (Amyloid
According to another modern concept (Dityatev and precursor protein) (Maltsev et al., 2014).
Schachner, 2003), a synapse is considered to be a four-part The novel hypothesis of the AD pathogenesis suggests that
structure, which additionally consists of an irreplaceable MERCs are involved in the initial phase of the disease, and their
component for providing neurotransmission, the extracellular altered functions contribute to cellular metabolic dysfunction.
matrix. However, there is no data concerning the direct In support of this, MERCs are considered to be an intracellular
connection between intracellular MERCs and the extracellular site of γ-secretase (APP cleavage enzyme) and presenilins
matrix related to neurotransmission. (γ-secretase subunit proteins) activity, which gene mutations
are associated with AD pathogenesis (Area-Gomez et al., 2009;
Area-Gomez and Schon, 2016). Loss of presenilins, in turn,
impairs glutamatergic neurotransmission from the presynaptic
THE EMERGING ROLE OF MERCs IN side (Zhang et al., 2009).
SUPPORTING NEUROTRANSMISSION Furthermore, it was demonstrated by Pera et al. (2017) that
DURING THE DEVELOPMENT OF in addition to γ-secretase, one of the APP cleavage fragments,
NEURODEGENERATION C99 (β-C-terminal fragment), is also localized in MAM. In line
with that, the accumulation of uncleaved C99 led to physical
Neurotransmission becomes substantially altered during the and functional stimulation of MERCs formation, increased
process of neurodegeneration (Bae and Kim, 2017). Synapses and sphingomyelinase activity in MERCs, and, subsequently, elevated
the machinery that provides the maintenance of their function ceramide content. Ceramide, in turn, is known as a proapoptotic
are especially vulnerable to chronic stress factors observed in molecule and mitochondrial respiration inhibitor (Pera et al.,
neurodegenerative pathologies. Taking into account the number 2017). The enzyme required for APP cleavage to Aβ and C99,
of cellular functions carried out with MERCs, it appears to ACAT (acyl-CoA: cholesterol acyltransferase) (Puglielli et al.,
be natural that mutant forms or altered functions of several 2004), is present in MAM (Area-Gomez et al., 2018). Thus, it is
resident proteins are implicated in the course of neurological supposed that MERCs are the cleavage site of APP. Mutations
pathologies (Veeresh et al., 2019). Such pathologies include in presenilin genes and disruption of γ-secretase activity can
proteinopathies (Poston et al., 2013; Paillusson et al., 2016) lead to the accumulation of C99 in MERCs, which are in direct
and metabolic disorders in Wolfram syndrome (Wiley et al., contact with mitochondria and can affect the functional status
2013; Delprat et al., 2018) and GM1-gangliosidosis (Sano et al., of organelles and, indirectly, intercellular signaling via synapses
2009). Abnormalities in the structure of the genes encoding (Picone et al., 2014; Schreiner et al., 2015).
MERCs-localized functional protein complexes appear to be an The early contribution of MERCs to the progression of AD
important part of neurodegeneration. For instance, SIGMA1R is also supported with the proteome analysis. Many MAM-
and PACS2 knockdown led to the neuronal degeneration in localized proteins are associated with AD (Völgyi et al., 2018),
murine hippocampal cultures, which demonstrates the important though the evidence related to the change of their content

and distribution in the brain appears to be controversial. The Ca2+ transfer to mitochondria. On the other hand, according
level analysis of SIGMA1R and PACS2 in mice with APPSwe/Lon to the evidence by Paillusson et al. (2017), overexpression of
mutations showed that levels of both proteins are elevated in both wild-type and mutant α-synuclein reduced the number of
the hippocampus before Aβ plaque formation and also increased ER-mitochondria connections. Moreover, the ability of mutant
in the cerebellum and cortex, but in this case after the plaque α-synuclein to interact with VAPB, disrupting the VAPB-
formation (Hedskog et al., 2013). On the contrary, in postmortem PTPIP51 complex, was associated with the negative regulation
cortical tissue of patients with AD the increase in PACS2 of the interaction between mitochondria and the ER (Paillusson
level was shown, but a decrease in the level of SIGMA1R et al., 2017). Along with the previous evidence, the demonstrated
(Hedskog et al., 2013). Besides, a life-time decline in SIGMA1R ability of α-synuclein to interact with, block, and translocate
distribution was demonstrated in the cerebral cortex of patients mitochondrial VDAC through the outer membrane of the
with AD already at the early stage of the disease (Mishina organelle can lead to the disruption of Ca2+ exchange through
et al., 2008). According to the recent evidence (Lau et al., MAM (Rostovtseva et al., 2015). Taking into consideration
2020), in cortical pyramidal neurons of AD-affected brain, the that multiple α-synuclein-involving mechanisms ultimately lead
complex of VAPB-PTPIP51 was shown to be disrupted, which to the dysregulation of MERCs-associated Ca2+ exchange, the
together with previous data can outline the events leading to expression of mutant protein in PD may strongly affect the
the altered Ca2+ transfer, ATP synthesis, and, subsequently, neurotransmission in the mitochondria-associated presynapses,
impaired function of synaptic transmission (Gómez-Suaga et al., since mitochondrial Ca2+ uptake stimulates ATP production,
2019). The increase in oxidative stress reactions was observed which is crucial to satisfy local energy demands during the active
along with the perturbed levels of MAM-localized proteins in synaptic transmission (Harris et al., 2012).
the cortex of murine AD models (Völgyi et al., 2018), which also Mitochondria-endoplasmic reticulum contacts can fail to
reflects a possible link between MERCs functions and impaired support the neurotransmission in PD not only due to
neurotransmission, since the increased production of reactive α-synuclein mutations, but also because of the local presence
oxygen species directly affects synaptic activity in neurons of mutant proteins with impaired functions. Indeed, PD-
(Ahmad et al., 2017). related mutations in Miro1 (Mitochondrial Rho GTPase 1),
a MERCs-localized protein (Modi et al., 2019), lead to the
Parkinson’s Disease decreased mitochondrial transport in neurons, increased ER-
Parkinson’s disease (PD) is a neurodegenerative disease mitochondrial tethering, and the adverse effect toward regulation
associated with the progressive degeneration of dopaminergic of mitophagy and Ca2+ homeostasis (Berenguer-Escuder et al.,
neurons in the pars compacta of the substantia nigra and 2020). Importantly, Miro1 is involved in the postsynaptic
the formation of intracellular protein inclusions – Lewy positioning of mitochondria in response to activated NMDA
bodies, as well as with Lewy neurites – neuronal processes receptors (Macaskill et al., 2009). Concerning the significant
characterized by dystrophy, with a significant role of the protein role in Ca2+ exchange between the ER and mitochondria, DJ-1
α-synuclein. Patients with PD suffer from motor disorders such protein that can induce MERCs formation was also highlighted,
as bradykinesia, tremors, muscle rigidity, and postural instability the dysfunction of which is associated with the development
(Gómez-Suaga et al., 2018). of PD. According to a recent study (Liu et al., 2019), DJ-1
The presence of α-synuclein was observed in MAM (Guardia- appears to be an important component supporting the complex
Laguarta et al., 2014), while α-synuclein-lacking neurons IP3R-GRP75-VDAC, providing an integrity and function of ER-
demonstrated a decreased number of MERCs and an increased mitochondria connection. Suppression of DJ-1 led to the negative
ER-mitochondria distance (Faustini et al., 2019). The evidence regulation of Ca2+ exchange between organelles (Ottolini
that mitochondrial morphology, the level of Mfn1 expression, et al., 2013) and impaired the ER-mitochondria association
and respiration capacity was affected in cortical neurons of related to interaction with the IP3R-GRP75-VDAC complex (Liu
mice lacking α-synuclein supports the hypothesis about a et al., 2019). Finally, as was mentioned above, SIGMA1R can
physiological interplay between this protein and the function of bidirectionally modulate the state of NMDA receptors, thus
mitochondria (Faustini et al., 2019). In addition, oligomerization exerting an influence on synaptic plasticity. Both experimental
of α-synuclein induces mitochondrial toxicity, fission, energy (Wilson et al., 2020) and theoretic (Yang et al., 2019) studies show
stress, and mitophagy, demonstrating the role of α-synuclein the link between SIGMA1R and the neurotransmission in PD.
as a therapeutic target for future studies (Ryan et al., 2015).
Many observations indicate that the accumulation of α-synuclein
in presynaptic terminals disrupts the functioning of synaptic Huntington’s Disease
proteins, synaptic plasticity, and neurotransmission, hence Huntington’s disease (HD) is an autosomal dominant inherited
inducing axonal damage (Ben Gedalya et al., 2009; Cheng et al., neurodegenerative disorder with a manifestation at the age of
2011; Anichtchik et al., 2013), which can be induced directly 35–50 years and symptoms including motor impairment and
with the effect of α-synuclein, or indirectly with MAM proteins progressive dementia. The pathogenesis of HD is associated with
being intermediates. On one hand, Calì et al. (2012) showed the accumulation of CAG repeats in exon 1 of the Huntingtin
that α-synuclein supports the ER-mitochondria interaction and protein (Htt) gene and the formation of mutant Huntingtin
thus is essential for the preservation of mitochondrial Ca2+ (mHtt), which contains polyglutamine tract (PolyQ) at the
homeostasis, while the mutant protein negatively influenced N-terminus. During the progression of HD the accumulation of

mHtt aggregates in the neuronal nucleus and, to a lesser extent, DISCUSSION

in the cytoplasm, dendrites, and axonal terminals is observed
(Ghosh and Tabrizi, 2018). Even though Htt and mHtt are In the last few years, multiple studies of mitochondria-
ubiquitously expressed in the brain, the development of HD is endoplasmic reticulum interactions in neuronal cells were
associated predominantly with impaired synaptic transmission carried out, and valuable data that elucidate the role and
(Smith-Dijak et al., 2019), selective loss of striatal neurons, and functions of MERCs related to synaptic transmission were
less markedly with loss of hippocampal and subthalamic neurons. obtained (Gómez-Suaga et al., 2019; Dematteis et al., 2020;
At the late stage of HD the cerebral cortex is also affected Liao et al., 2020; Perrone et al., 2020). Numerous data confirm
(Reddy et al., 2009). the participation of MERCs in the regulation of cell functions
As well as in AD and PD, during the HD progression, the such as calcium and lipid homeostasis, fission and mobility
content of MERCs-localized proteins is changed. At the early of mitochondria, autophagy, and the initiation of apoptosis,
and middle stages of HD, IP3R3, and GRP75 were shown in particular, in neuronal cells. The data altogether reflect
to be reduced in the striatum, while Mfn2 was decreased the potential implication of MERCs in supporting active
only in the putamen (Cherubini et al., 2020). The supposed neurotransmission, indicating the role of these intracellular
participation of MERCs in the pathogenesis of HD is also contacts as an assistant to neurotransmission. Even though
associated with the influence that mHtt exerts on mechanisms MERCs can be present inside the vast majority of neuronal
of ER-mitochondria Ca2+ exchange, Ca2+ capacity, and the cells and in different parts of the synapse, their role in
maintenance of Ca2+ homeostasis in brain cells. In the cortex the neurotransmission may be underestimated or not taken
and striatum of murine HD models, impaired interaction into account.
between IP3R1 and GRP78 (BiP) was shown (Higo et al., 2010). The analysis of literature related to the topic revealed
wtHtt together with HAP-1 (Huntingtin-associated protein 1), several issues connected with studying MERCs in neuron-
or Htt separately, can form a complex with the C-terminus glial networks. The data are insufficient not only to separate
of IP3R1, which leads to its sensitization toward IP3 and the function of proteins in intracellular contacts and free
promotes Ca2+ release from the ER (Tang et al., 2003). Calcium membranes, but also to characterize the differences of MERCs
depletion in the ER, in turn, can stimulate CRAC (Calcium in various parts of the neuron, types of glial cells, and brain
release-activated channels) opening and, subsequently, the store- areas. There is still a lack of elegant experiments elucidating
operated calcium entry (Prakriya and Lewis, 2015), which was the role of MERCs precisely in synaptic transmission. Despite
induced in transgenic HD mice (Vigont et al., 2014, 2015). Htt multiple studies carried out, there are still several questions
and mHtt localization in striatal cells were associated with the that have yet to be answered. For example, is there but
outer mitochondrial membrane (Choo et al., 2004). Accordingly, one type of MERCs that could be functionally modified, or
Ca2+ capacity, the amount of Ca2+ , which mitochondria can MERCs with different cleft width fulfill specific functions from
store before mitochondrial permeability transition pore opening the very beginning without the possibility of restructuring?
and the release of proapoptotic factors into the cytoplasm, was It also appears to be yet unknown, whether some of the
significantly reduced after the PolyQ (Panov et al., 2002) and described proteins are localized directly in MAM or if their
truncated N-terminal mHtt (Choo et al., 2004) exposure. Finally, presence in the MAM’s fraction is merely a consequence of the
under conditions of impaired Ca2+ homeostasis, the pathological imperfect fractionation methods. New methods, such as split-
fragmentation of mitochondria is observed (Shirendeb et al., BioID (Kwak et al., 2020) that can detect MAM’s regulatory
2012) upon interaction between mHtt and Drp1 (Costa et al., proteins and reveal the proteome of synaptic intracellular
2010). The evidence provided by Cherubini et al. (2020) supports contacts are required. Finally, it remains to be poorly understood
the hypothesis that increased mitochondrial fragmentation whether altered MERCs functions are primary or secondary
and reduced ER-mitochondria association in HD striatum to the development of neurodegeneration. The MERC’s role
are interconnected. Moreover, a possible connection between of assistant to neurotransmission confirmed, but still requires
impaired mitochondrial dynamics, reduced synaptic activity, and further study.
the proteins of MERCs in HD was demonstrated (Manczak
and Reddy, 2015). Interestingly, the treatment with Mdivi1
(mitochondrial division inhibitor 1) rescued abnormally up- AUTHOR CONTRIBUTIONS
regulated genes of MERCs-related fission proteins (Drp1, Fis1),
down-regulated fusion genes (Mfn1, Mfn2), which not only OS designed the study. OS and PP collected and analyzed the
subsequently normalized the function of mitochondria but also data, wrote and revised the manuscript. IM supervised the study
led to the up-regulation of synaptic genes in mHtt-neurons and conceptualized the idea. All authors contributed to the article
(Manczak and Reddy, 2015). Thus, according to the findings and approved the submitted version.
mentioned above, the impaired function of several MERCs
proteins can contribute to the mitochondrial dysfunction and
neuronal vulnerability and loss observed in HD. However, FUNDING
the data presented up to date are limited; hence the role of
MERCs in the contribution to altered neurotransmission in HD The research was conducted with financial support from RFBR as
requires further study. a part of a science project No. 18-34-00877.

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published: 09 November 2020

MERCs. The Novel Assistant to

In neuroscience, much attention is paid to intercellular interactions, in particular, to

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Frontiers in Neuroscience | www.frontiersin.org 2 November 2020 | Volume 14 | Article 589319

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the general stimulation of presynaptic function (Dason et al., Astrocytic Support

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mHtt aggregates in the neuronal nucleus and, to a lesser extent, DISCUSSION

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Frontiers in Neuroscience | www.frontiersin.org 10 November 2020 | Volume 14 | Article 589319

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Frontiers in Neuroscience | www.frontiersin.org 13 November 2020 | Volume 14 | Article 589319

Frontiers in Neuroscience | www.frontiersin.org 14 November 2020 | Volume 14 | Article 589319

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