Roles of sigma-1 receptors on mitochondrial functions relevant to neurodegenerative diseases
Weng et al. Journal of Biomedical Science
Roles of sigma-1 receptors on mitochondrial functions relevant to neurodegenerative diseases
Tzu-Yu Weng 0 1 2
Shang-Yi Anne Tsai 0 2
Tsung-Ping Su 0 2
0 Cellular Pathobiology Section, Integrative Neuroscience Branch, Intramural Research Program, National Institute on Drug Abuse, NIH, DHHS, IRP, NIDA/ NIH , Triad Bldg. suite 3512, 333 Cassell Drive, Baltimore, MD 21224 , USA
1 Genomics Research Center , Academia Sinica, Taipei , Taiwan
2 Authors' information Tzu-Yu Weng
The sigma-1 receptor (Sig-1R) is a chaperone that resides mainly at the mitochondrion-associated endoplasmic reticulum (ER) membrane (called the MAMs) and acts as a dynamic pluripotent modulator in living systems. At the MAM, the Sig-1R is known to play a role in regulating the Ca2+ signaling between ER and mitochondria and in maintaining the structural integrity of the MAM. The MAM serves as bridges between ER and mitochondria regulating multiple functions such as Ca2+ transfer, energy exchange, lipid synthesis and transports, and protein folding that are pivotal to cell survival and defense. Recently, emerging evidences indicate that the MAM is critical in maintaining neuronal homeostasis. Thus, given the specific localization of the Sig-1R at the MAM, we highlight and propose that the direct or indirect regulations of the Sig-1R on mitochondrial functions may relate to neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS). In addition, the promising use of Sig-1R ligands to rescue mitochondrial dysfunction-induced neurodegeneration is addressed.
Sigma-1 receptor; Mitochondria; Mitochondrion-associated ER membrane (MAM); Neurodegenerative disorders
The sigma-1 receptor (Sig-1R) is an endoplasmic
reticulum (ER) chaperone protein located primarily at the
mitochondrion-associated ER membrane (MAM) that
plays a variety of important roles in the cell. One of the
functions of the Sig-1R is to regulate Ca2+ signaling
between the ER and mitochondria for example by coupling
to ankyrin B and inositol 1,4,5-trisphosphate receptor
]. Sig-1R acts in an agonist/antagonist-sensitive
manner to coordinate the coupling of ankyrin B to type 3
IP3R (IP3R3) to control Ca2+ signaling. The signaling
pathway between Sig-1Rs, IP3R3s, and Ca2+ was found to
relate to cellular survival against ER stress. When facing
ER stress, the Sig-1R dissociates from cognate
cochaperone BiP and acts as a free chaperone to stabilize
IP3R3s to increase Ca2+ signaling from ER into
mitochondria to facilitate the production of ATP [
]. The Sig-1R
also regulates Ca2+ influx by attenuating the coupling of
the ER Ca2+ sensor STIM1 to Orai1 [
]. Crottès et al.
studied the relationship between Sig-1R and ion channels
in cancer cells, they reported that cancer cells expressed
active Sig-1Rs that modulated a variety of ion channel
]. Sig-1Rs effectively altered the cell’s electrical
plasticity, allowing the cell to become better suited for
survival in a cancerous environment. The Sig-1R has also
been implicated as an ion channel regulator in
amyotrophic lateral sclerosis (ALS), a neurodegenerative disease
that affects motor neurons. It was recently shown that
motor neurons have the highest levels of Sig-1Rs in the
central nervous system (CNS), and that Sig-1Rs may help
direct the flow of ions through potassium channels [
This would be a way of reducing the excitability of motor
neurons, therefore slowing the progression of ALS.
As well related to the ALS example, the Sig-1R may
involve in the development and maintenance of axons
and neurons. Sig-1R-lipid interactions are important in
both oligodendrocyte (OL) differentiation and axon
extensions. Sig-1Rs target galactosylceramide
(GalCer)and cholesterol-enriched lipid microdomains on the ER
of OLs, and may thus modulate myelination by
controlling the dynamics of the lipid transport to the myelin
]. Recently, Tsai et al. reported that the
Sig1R can modulate tau phosphorylation and axon
development through an association with myristic acid and the
cdk 5 activator p35 [
]. The Sig-1R binds myristic acid
to facilitate the myristoylation of p35 and promote the
p35 turnover which, as a result, reduces the available
p25 which would otherwise over-activate cdk5 leading to
the hyperphosphorylation of Tau and retardation of axon
growth. Hippocampal dendritic spine formation is also
regulated by Sig-1Rs. The redox state of neurons
determines the activity of the
ER-mitochondrion-TIAM1Rac1 GTP signaling pathway that is a component of
dendritic spine development. The Sig-1R plays a part in
this process by scavenging free radicals that would
otherwise cause oxidative stress at the beginning of the
pathway and attenuate dendrite formation .
Dysregulation of axonal maintenance may cause
neurodegenerative and psychiatric disorders, such as
Alzheimer’s disease (AD), Parkinson’s disease (PD), and
schizophrenia. It has been shown that functional Sig-1Rs
can help mitigate symptoms of some neurodegenerative
disorders, although they can also be involved in the
establishment of certain other diseases [
]. For this
reason, Sig-1R ligands, both agonists and antagonists, are of
great interest as potential therapeutic agents against
The Sig-1R has also been shown to help protect cells
from mitochondria-derived reactive oxidative species
(ROS) associated damages. IRE1 is one of three ER stress
sensors specifically located at the MAM to respond to
stress caused by mitochondria or ER-derived ROS [
Upon ER stress, IRE1 undergoes dimerization and
phosphorylation leading to its active endonuclease form.
IRE1 then splices XBP1 mRNA with the end result being
an upregulation of ER chaperones that can help mitigate
stress. The Sig-1R mediates this process by stabilizing
IRE1 during its activation.
The Sig-1R has an important function in regulating
gene transcription. It was discovered that the Sig-1R,
which normally localizes at the ER, can translocate to
the nuclear envelope where it binds emerin that in turn
recruits barrier-to-autointegration factor (BAF) and
histone deacetylase (HDAC) to form a complex with
specific protein 3 (Sp3) which can then suppress the gene
transcription of monoamine oxidase B (MAOB) [
Thus, the Sig-1R plays a role in the mediation of many
cellular functions, making it a protein of great interest
for treatments of neurological disorders.
Sig-1R regulates mitochondrial functions
Mitochondria are intracellular “powerhouse” organelles
responsible for certain biogenesis and fundamental cellular
energy processes [
]. Unlike other organelles in the cell,
they are pretty much functionally autonomous since
mitochondria have their own set of genomes mitochondrial
DNA (mtDNA) [
], and can generate cellular energy.
Most scientists prefer the endosymbiotic theories that the
mitochondrial origin traces back to 1.5 billion years ago,
arising from the endosymbiotic α-proteobacteria, in which
free-living proteobacteria were taken inside another cell to
form an endosymbiont and later evolved into an organelle
]. Mitochondria contain multiple membrane
compartments like their ancestors, including outer membrane,
intermembrane space, inner membrane, boundary
membrane, cristae and matrix [
]. Mitochondrion is also a
dynamic organelle with constitutive fission, fusion, and is able
to migrate or undergo mitophagy for manipulating the
population of mitochondria and maintaining the metabolic
homeostasis in different metabolic states [
Mitochondrion is noted as a main source of ATP
through oxidative phosphorylation that takes place in
the inner membrane, comprising a series of respiratory
chain complexes work cooperatively to drive the ATP
]. Apart from this, other metabolic
process such as citric acid cycle (TCA cycle or Krebs
cycle), synthesis of the heme groups and β-oxidation of
fatty acids all occur in mitochondria [
also play important role in the Ca2+ signaling [
production of ROS [
] and cellular apoptosis [
Therefore, mutation of the genes in mtDNA or nuclear genes
coding for the metabolic process as well as dysfunction
of some direct or indirect regulations of the
mitochondrial proteins can lead to mitochondrial dysfunctions,
causing multiple symptoms and diseases [
The discovery of MAM dated back in the late 1950s
when the association between ER and mitochondria was
first identified by the electron microscopic examination
in fish gills [
]. Subsequent studies with a sequel of
improved protocols led to the isolation and characterization
of biochemically distinct domains of ER-interacting
]. To date, it is generally recognized that
ER and mitochondria form contact sites via proteins that
tether ER and mitochondrial membranes [
microdomains at ER-mitochondria junctions govern
diverse cellular functions such as Ca2+ transfer, energy
exchange, lipid synthesis and transports, and protein
folding that are pivotal to cell survival and defense. Residing
at the ER-mitochondra contact sites, Sig-1Rs not only
regulate ER Ca2+ levels and protein degradations, they also
govern cellular activities that take place within that
specific MAM domain. Therefore, the Sig-1Rs serve as a
communicator that bridges these two organelles and plays
pivotal roles in mitochondrial functions. The Sig-1R and
the mitochondrion both play multiple roles in the cell.
Mitochondria are the main regulator of cell survival/death
as well as that for the ROS production. How Sig-1Rs exert
their cellular activities through direct or indirect
regulations of mitochondrial functions will be described and/or
proposed as follows.
Maintains mitochondrial integrity
Microdomain of high Ca2+ ion concentration is
transiently generated in proximity to IP3 (inositol
1,4,5-trisphosphate)-sensitive channels and is surveyed by nearby
]. This microdomain for efficient
Ca2+ transfer is called mitochondrial associated ER
membrane (the MAM) [
]. Ca2+ ion releasing from
ER into the mitochondrial matrix can affect
mitochondrial functions including the activation of metabolic
enzymes for ATP production and the promotion of
apoptosis cascades . In the resting state, Sig-1Rs
form a complex with the chaperone BiP at the MAM
(Fig. 1a). Upon the ER Ca2+ depletion or the Sig-1R
agonist stimulation, Sig-1Rs dissociate from BiP to
chaperone IP3R3s, leading to a prolonged Ca2+ transfer
from ER into mitochondria. Sig-1Rs can also translocate
from the MAM to the entire ER network under
continuously low ER Ca2+ concentration such as that caused by
ER stress [
]. A splice variant of Sig-1R which lacks 47
ribonucleotides encoding for exon 2 forms a complex
with Sig-1R but not with IP3R in the MAM. Therefore,
overexpression of this variant interferes with normal
Sig1R functions such as the mitochondrial IP3R-mediated
Ca2+ uptake. The Sig-1R variant also suppresses
mitochondrial ATP production following ER stress, thus
enhancing cellular apoptosis [
]. Overexpression of
another Sig-1R variant, E102Q, impairs mitochondrial
ATP production and elicits neuronal cell death [
These findings indicate that the Sig-1R regulates
mitochondrial homeostasis, and some of the
Sig-1Rinteracting proteins may reside in the mitochondria.
Using immunoprecipitation assay, Sig-1R was found to
interact with mitochondrial Rac1 which is a critical
regulator for neurogenesis, and formed complexes with
IP3R and Bcl-2 in isolated mitochondria [
Sig1R agonist (+)-pentazocine further increased this
interaction while the antagonist haloperidol cannot.
(+)-Pentazocine also led to the phosphorylation of Bad and the
NADPH-dependent production of ROS, suggesting that
Sig-1R might act through the Rac1 signaling to induce
mild oxidative stress and cell survival pathways. The
roles of Sig-1Rs on restoring Ca2+ transferring into
mitochondria, ATP productions, and mitochondrial
morphology have also been demonstrated in the Sig-1R agonist
SA4503-treated cardiomyocytes [
Sig1Rs play an important role in maintaining mitochondrial
integrity as the aberrant neuronal mitochondrial
aggregates or fragments have been associated with Sig-1R
deficiency. Silencing of Sig-1Rs in hippocampal neurons
leads to shorter and smaller mitochondria as well as
aberrant mitochondria membrane potentials [
Improves cell survival and stress response via mitochondria
Mitochondrial metabolism is closely related to several of
the critical cellular functions including survival or
apoptosis. The mitochondrial Ca2+ surge from the ER
causes a mitochondrial Ca2+ overload, thus stimulating
mitochondria to release multiple apoptotic factors such
as cytochrome c that in turn activates caspase and leads
to apoptosis [
]. The anti-apoptotic Bcl-2 family plays
crucial roles in determining cellular survivals against
apoptotic pathway [
]. It was found that the Sig-1R
promoted cellular survival by regulating the Bcl-2 which
at least in part exists on mitochondria, while silencing of
Sig-1Rs down-regulated Bcl-2 mRNA expression and the
effects were rescued by ROS scavengers or the inhibitor
of the ROS-inducible transcription factor nuclear factor
κB (NF-κB). Silencing of Sig-1Rs also enhanced
hydrogen peroxide (H2O2)-induced cell apoptosis [
agonists protected neurons against the insults caused by
oxygen–glucose deprivation or glutamate stimulation
through the Bcl-2 pathway [
]. The transcriptome
analysis revealed that Bcl-2 levels decreased in the Sig-1R
KO retina [
]. In addition to the Bcl-2 family, Sig-1Rs
protected retinal ganglion cell against glutamate-induced
cell apoptosis by regulating Ca2+ signaling and inhibiting
the activation of pro-apoptotic factors such as Bax and
]. Conversely, knocking down Sig-1Rs in
neurons caused a decrease of mitochondrial membrane
potential and the release of cytochrome c, leading to
disrupted cytoskeleton networks and the consequential
immature formation of dendritic spines [
]. The Sig-1R is
also involved in the pro-apoptotic pathways. Sig-1R
ligands haven been shown to induce tumor cell death
through the activation of caspase cascades, Ca2
+-dependent activation of phospholipase C (PLC), Ca2
+-independent inhibition of PI3K signaling [
], or the
HIF-1α pathway [
]. Methamphetamine induced
microglia apoptosis by activation of the MAPK, PI3K/Akt and
p53 pathways, while blockage of the Sig-1R suppressed
pro-apoptotic factors such as Bax, caspase-3 and
caspase9 induced by methamphetamine [
ER stress stimulates cells to activate the unfolded
protein response (UPR) to cope with the stress resulting
from accumulation of unfolded proteins in the ER [
Early phases of ER stress trigger an increase in
mitochondrial ATP levels and oxygen consumption which
depend critically on the ER-mitochondrion coupling and
Ca2+ transfer from ER into mitochondria [
implying the metabolic regulation of mitochondria by the ER.
The three major sensors of the UPR are PERK, IRE1 and
ATF6 . Sig-1Rs stabilized IRE1 at the MAM when
cells were under ER stress. Deficiency of Sig-1R caused
cell apoptosis by compromising the IRE1-XBP1
signaling. Treatment of cells with mitochondrial ROS inducer,
antimycin A, showed that the mitochondrial-derived
ROS triggered the IRE1-XBP1 signaling but not the
ATF6 or PERK signaling pathway toward Sig-1Rs [
was suggested that the mRNA of ATF6 showed
profound changes in the retinal Müller glial cells isolated
from Sig-1R KO mice [
], and microarray analyses
revealed that silencing of Sig-1Rs influenced the
expression of genes related to the ER pathway in primary
hippocampal neurons [
]. Ligand such as
(+)-pentazocine could attenuate the mRNA level of ER stress
proteins PERK, ATF4, ATF6, IRE1, and CHOP that were
upregulated in retinal ganglion cells exposed to oxidative
]. ATF4 also interacted with the 5′ flanking
region of SIGMAR1, and transcriptionally regulated the
Sig-1R in the PERK/eIF2α/ATF4 pathway under ER
], moreover, fluvoxamine, a selective serotonin
reuptake inhibitor with affinity for Sig-1R, induced
Sig1R expression involving ATF4 without invoking the
PERK pathway [
Regulates oxidative stress derived from mitochondria
Free radicals play pivotal biological roles in cells
including signal transduction, gene transcription and
enzymatic activity regulation. However, unbalanced ROS
productions in neuronal microenvironments caused free
radical-induced lipid and protein modifications and
DNA damages, generated many byproducts that are
harmful to the cells, and led to manifestation of
neurodegenerative diseases [
]. The mitochondrion is one of
the main sources that produces oxidants in cells via
consumption of O2 in the aerobic respiration [
might wonder how the Sig-1R counterbalances the
excess ROS. The Sig-1R has been reported to regulate
oxidative stress responses and involve thus in the regulation
of neuroplasticity through Rac1 GTPase. Paradoxically
however, treatment of bovine brain mitochondria with
Sig-1R agonist (+)-pentazocine led to the
NADPHdependent production of ROS [
]. Activation of
Sig1Rs through agonists has been reported to mitigate
cellular stress. For example, the Sig-1R agonist blocked
lipid peroxidation in β-amyloid (Aβ) peptide-injected
], reduced nitrosative and oxidative stress on
proteins after traumatic brain injury (TBI) [
mitigated the oxidative stress-induced cell death in human
lens cell line [
]. These observations implicate the
involvement of Sig-1Rs in neuroprotection. Emerging
evidence provides insights to the underlying mechanisms of
oxidative insults mediated by Sig-1Rs. A report showed
that higher levels of ROS were observed in the livers,
lungs and hepatocytes of Sig-1R KO mice when
compared to that from the WT mice, suggesting that the KO
mice were under oxidative stress. Antioxidant protein
peroxiredoxin 6 (Prdx6) and the ER chaperone BiP were
also increased in Sig-1R KO animals. Further analysis
revealed that Sig-1R may upregulate NADPH quinone
oxidoreductase 1 (NQO1) and SOD1 mRNA expression
through antioxidant response element (ARE) [
transcription factor Nrf2 (nuclear factor erythroid
2related factor 2) binds to the ARE and regulates genes
that are involved in cellular protection against oxidative
stress-induced cell death [
]. Silencing of Sig-1Rs in
primary hippocampal neurons also induced expression
of genes related to the Nrf2-mediated oxidative stress
pathway as shown from a microarray analysis [
Additionally, in a cellular model using Sig-1R KO Müller glia
cells, the ROS levels were increased in KO cells with a
concomitant reduced level of Nrf2 and the resultant
Nrf2-ARE binding affinity [
]. Several genes involved in
the mitochondrial metabolic process are
transcriptionally regulated by Nrf2; therefore, Nrf2 also affects
mitochondrial functions such as mitochondrial membrane
potential, ATP synthesis, and mitochondrial fatty acid
]. Although Nrf2 is considered as a
transcription factor, it has been proposed that Nrf2 protects
mitochondria from oxidant stress possibly through
direct interaction with the mitochondrial outer membrane
]. Moreover, a zinc finger protein 179 that has been
identified as a Sig-1R downstream effector, exhibiting a
neuroprotective role in the H2O2-induced ROS insult
]. The exact interactive connections between
Sig-1R, Nrf2 and mitochondria as well as other
neuroprotective mechanisms of Sig-1Rs in combating ROS
remain to be totally clarified.
Regulates autophagy via mitochondria
Autophagy is triggered upon cells are under stress such
as nutrient starvation, ER stress, and pathogen
infection. It is the process that cells strive for survival by
invoking self-degradation of cellular components in
which double-membrane autophagosomes engulf
protein aggregates, organelles, portions of cytoplasm and
fuse with lysosomes for energy demand [
stress damages mitochondria while mitochondrion itself
is also a substrate of autophagy, namely, mitophagy
]. There are molecules that may provide link of
autophagy to the MAM including IP3R which its
signaling is required to maintain the autophagy suppression.
Lack of IP3R decreased mitochondrial Ca2+ uptake and
activated autophagy in the AMPK pathway [
Part of the mitophagy is initiated when PINK1 recruits
Parkin that targets mitochondria, causing the
ubiquitination of the mitochondrial outer membrane protein
voltage-dependent anion channel 1 (VDAC1) that is
further recognized by p62 for degradation [
Moreover, it is also suggested that autophagy originates
from the MAM where nucleation of the isolation
membrane may occur [
]. Therefore, emerging evidences
suggest the role of the Sig-1R in autophagy. The Sig-1R
(IPAG) or haloperidol stimulated UPR and autophagic
flux that depended on Sig-1R in a time-lapsed manner.
UPR induction preceded autophagosome formation,
and inhibition of UPR or autophagy accelerated cellular
apoptosis that induced by antagonizing Sig-1R activities
]. Silencing or loss of Sig-1Rs led to widened ER
morphology, dissolution of mitochondrial cristae
structure, and enhanced mitophagy in cells that were
accompanied with impaired fusion between autophagosome
and lysosomes, lipid raft destabilization, and impaired
endolysosomal pathways [
]. Leptomycin B and
thapsigargin caused the sequestration of Sig-1R within the
nucleus with a resultant partial co-localization with p62
which is an important mediator in the proteasome and
autophagy degradation systems [
]. Silencing of Sig-1Rs or
employing the Sig-1R antagonist also demonstrated that
cocaine, a Sig-1R agonist, induced autophagy in astrocytes
through the Sig-1R mediated pathway [
treatment of the Sig-1R antagonist increased the expression of
the monosialotetrahexosylganglioside (GM1) and the
accumulation of GM1 in the autophagosomes,
demonstrating a relation between Sig-1R and gangliosides [
Interestingly, silencing of Sig-1Rs blocked autophagy at
the isolation membrane expansion/LC3 lipidation stage
], implicating the association of Sig-1R with the
formation of autophpagy at the MAM as well as its ability to
Regulates lipid transport and steroidogenesis via mitochondria
It has been demonstrated that certain lipids are imported
into mitochondria, for instance, phosphatidylserines are
imported into mitochondria from the MAM contact sites
to decarboxylate to phosphatidylethanolamine [
Sig1Rs participate in the lipid synthesis and can bind simple
sphingolipids such as ceramides [
]. MAM are enriched
in cholesterol and sphingolipids, and form MAM-derived
detergent-resistant membranes. Those detergent-resistant
microdomains also regulate the anchoring of Sig-1R to the
MAM. Sig-1Rs can interact with steroidogenic acute
regulatory protein (StAR) and the voltage-dependent anion
channel 2 (VDAC2) [
] which is a member of the
mitochondrial porin family that transports metabolites across
the mitochondrial outer membrane [
]. At the
MAM, VDAC2 regulates and interacts with StAR as a
critical step to transport cholesterol into mitochondria for
steroidogenesis . Noteworthy, another study indicated
that silencing of Sig-1Rs did not change the expression of
ER and mitochondrial resident proteins but led to the
reduced synthesis of pregnenolone. The interaction of the
Sig-1R between VDAC2 and StAR, suggesting a role of
Sig-1Rs in cholesterol trafficking and steroidogenesis at
the MAM [
]. Recently, it was also demonstrated that
the Sig-1R can directly interact with myristic acid,
promote p35 turnover, and regulate Tau phosphorylation and
axon extension [
]. The exact relation between Sig-1Rs
and other lipids at the MAM remains to be clarified.
Putative Sig-1R interacting proteins in mitochondria
Bioinformatics analyses identified several putative Sig-1R
interacting proteins in mitochondria [
cytochrome C1 (CYC1), prohibitin (PHB), solute carrier
family 25 member 11 (SLC25A11) and solute carrier
family 25 member 39 (SLC25A39) [
]. Some of these
proteins were demonstrated to be involved in the
neurodegenerative disease or cellular protection. CYC1 is a
subunit of mitochondrial complex III, playing roles in
response to oxidative stress and the generation of
superoxide anion in the mitochondrial respiratory chain [
]. CYC1 is also identified as neuroglobin binding
protein and the CYC1-neuroglobin association may be
involved in the ATP production [
PHB families control cell proliferation, cristae
morphogenesis and can regulate the fusion machinery of
]. SLC25 belongs to a family of transporters
that functions in the shuttling of the metabolites across
the inner mitochondrial membrane [
]. Inhibition of
the SLC25A11 function decreased the mitochondrial
GSH level in cerebellar astrocytes [
]. However, the
direct demonstration of those proteins’ interactions with
Sig-1Rs need to be investigated; so do the functional
consequences of those interactions.
Mitochondrial-associated neurological disorders and Sig-1R
Neurons and muscle cells contain high levels of
mitochondria due to a high demand of energy. The CNS has a
high rate of metabolism because neurons participate in
facilitating the neurotransmission and extending axons and
dendrites to neighboring cells for impulse transmission.
Neurons exert plasticity, exhibiting complex
morphologies, and constitutively undergo synaptic modulations
when stimulated. Therefore, mitochondrial dysfunction
can be detrimental to neurons [
] and has been
extensively discussed in neurodegeneration [
23, 89, 90
Disruptions of the microdomains at ER-mitochondria contacts
were found to relate to many neurological disorders [
]. Mechanisms involved in the progression of these
diseases include dysfunction of mitochondria, imbalance of
the Ca2+ homeostasis, ER stress, oxidative stress and
autophagy. Stationed at the MAM, the Sig-1R acts as an
intracellular organelle modulator between ER,
mitochondria, nucleus, and the plasma membrane upon
]. The Sig-1R is associated with many
neurological disorders [
], including AD , PD
], ALS [
], HD [
], stroke/ischemia [
neuropathic pain , and certain psychiatric disorders [
Emerging evidences suggest that Sig-1R functions as an
amplifier of intracellular signaling [
]. Sig-1R KO
impaired neurogenesis in mice with depressive-like
immobility phenotype [
]. Deficiency of Sig-1Rs aggravates
the progression in many neurodegenerative models, while
reinstating Sig-1Rs or agonistic activation restores neuronal
functions and alleviates disease progression. How Sig-1Rs
may regulate neurodegenerative diseases via a direct or
indirect regulation on mitochondria, especially via the MAM,
is described in the following sections.
Sig-1R in AD
The major symptoms of AD include selective cognitive
decline and memory loss, which are now accepted as
being caused by the Aβ plaques and the tau neurofibrillary
tangles. Aβ is generated from the serial enzymatic
digestion of amyloid precursor protein (APP) which has been
found to accumulate in the mitochondrial import
channel in AD brains [
]. Aβ also accumulates in the
mitochondria of AD patients and APP transgenic mouse
], and is associated with elevated H2O2 and
decreased cytochrome c oxidase activities in an animal
]. Aβ affects mitochondrial response to
metabolic status by interacting with mitochondrial enzyme or
disrupts synaptic functions by attenuating mitochondrial
]. Recently, it has been demonstrated
that Aβ is generated intracellularly at MAM and may
influence ER, mitochondrial and the MAM’s function
. Afobazole, a Sig-1R agonist, could lessen the
increased Ca2+ caused by Aβ25–35 through the activation
of Sig-1R. Afobazole reduced NO production, prevented
upregulation of the proapoptotic protein Bax, activated
caspase-3, and inhibited the downregulation of Bcl-2
induced by Aβ25–35 [
]. Up-regulation of Sig-1R was
found in the APPSwe/Lon mouse brain prior to the plaque
formations, while decreased Sig-1R protein levels were
observed in the human cortical postmortem brain tissue
]. The Sig-1R expression is critical to the coupling
of the ER-mitochondria contacts since the activation of
Sig-1R in Aβ-treated cells significantly increased the Ca2
+ shuttling from ER into mitochondria. Aβ also
increased the expression of MAM-associated proteins
such as IP3R3 and increased ER-mitochondria contacts
in hippocampal neurons. Similar results were found in
PET scan studies, in which Sig-1R expressions were
lower in the brain of early AD patients [
]. On the
other hand, the mitochondrial cholesterol influx was
increased with concomitantly increased levels of Sig-1R
and VDAC at MAMs in an old AD mouse model,
indicating a relation of those MAM proteins in cholesterol
]. Protein phosphatase 2A (PP2A)
interacts with IP3R3 and Akt, and can regulate IP3R3
phosphorylation state [
]. In a brain endothelial cell
culture model, okadaic acid-induced PP2A inhibition
was accompanied by elevations of phosphorylated tau,
ER stress markers, and Sig-1Rs as well as the Ca2+
overload in the mitochondria [
]. Brain vessels from
3xTgAD mice also showed decreased PP2A. Apolipoprotein E
(APOE) is another risk factor that is implicated in AD.
The polymorphism analysis revealed that SIGMAR1 and
APOE may interact to influence the severity of AD
]. Further, it was demonstrated that the
ER–mitochondrion communication and the function of the
MAM are increased significantly in cells treated with
astrocyte conditioned medium containing APOE4 [
suggesting a link to the Sig-1R. γ-Secretase complex is
one of the enzymes that engages in the processing of
APP to produce Aβ. The subunits of the γ-secretase
complex, presenilin-1 (PS1) and presenilin-2 (PS2), have
been found to localize at the MAM [
MAM activity was detected in mouse embryonic
fibroblasts lacking PS1 and PS2 [
]. Overexpression or
down-regulation of PS2 caused the fluctuation of Ca2+
concentrations between ER and mitochondria [
the tissues of an AD-associated mutant, PS1-E280A, the
ER-mitochondrion tethering was impaired and
voltagegated P/Q-type Ca2+ channels, IP3Rs and Ca2+-dependent
mitochondrial transport proteins were reduced as well.
Overexpression of this mutant altered the
ERmitochondrion tethering and associated transport in the
neuronal cell [
]. Tau proteins may be involved in the
pathogenesis of AD through their detrimental effect on
]. However, the association of tau
and Sig-1R as well as the PS processing mechanism
mediated by Sig-1R have yet to be established.
Sig-1R in PD
Parkinson’s disease is a slowly progressing disorder,
causing impaired motor functions such as bradykinesia or
tremor, and other non-motor complications. The
pathological characteristic of PD is the deposit of Lewy bodies
composed of α-synuclein, ubiquitin and neurofilaments
]. α-Synuclein [
], Parkin, PINK1 [
], DJ-1 [
] and LRRK2 [
] have been
demonstrated to be closely linked to the mitochondrial-related
Sig-1R expressions were lower in putamen of PD
patients as demonstrated by PET studies [
toxicity is involved in the etiology of PD. Dopamine
activated NF-κB while Sig-1Rs counteracted and inhibited
the proteasomal conversion/activation of NF-κB.
Silencing of Sig-1Rs in combination with dopamine treatment
caused a synergistic proteasomal conversion of NF-κB
p105 to the active form of p50, which is known to
down-regulate Bcl-2 at the transcriptional level.
Dopamine caused apoptosis in Sig-1R knockdown cells and
the effects could be reversed by overexpression of Bcl-2
]. Accumulation of α-synuclein impaired
mitochondrial complex I activity, and caused the release of
cytochrome c and the elevation of mitochondrial Ca2+, nitric
oxide (NO) and ROS concentrations [
Moreover, α-synuclein controls mitochondrial Ca2+
homeostasis by enhancing the ER-mitochondria associations 
and was later found to exist at the MAM where it
modulates the mitochondrial morphology [
Pailluson et al. demonstrated a closer link between
MAM and PD [
]. Vesicle-associated membrane
protein-associated protein B (VAPB) is an ER-resident
protein and protein tyrosine phosphatase interacting
protein 51 (PTPIP51) is an outer mitochondrial
membrane protein. Both proteins function as a bridge
tethering the ER and mitochondria. Residing at the MAM,
αsynuclein also interacts with VAPB but not PTPIP51.
Silencing of α-synuclein does not alter ER-mitochondria
associations, while overexpression of wild-type and
familial PD mutant α-synuclein disrupts the tethering
between VAPB and PTPIP51 to loosen the
ERmitochondria contacts. The actions of α-synuclein
include the loss of MAM domain, disruption of Ca2+
transferring between the two organelles, and the
inhibition of ATP production. Neither expression of
WT/mutant nor silencing of α-synuclein changed the protein
expression of Sig-1R, indicating that α-synuclein may
not influence the translational level of Sig-1R [
However, it remains to be investigated if the
αsynuclein-induced reduction of the ER-mitochondria
associations may involve the Sig-1R. Parkin and PINK1
work cooperatively to regulate the homeostasis of
mitochondria, such as mitochondrial fission/fusion
machinery, the integrity of mitochondria or mitophagy [
]. DJ-1 exerts its neuroprotection by regulating
the function of mitochondria , and its mutation
also caused a reduction in the level of ATP [
and DJ-1 can both alter the ER-mitochondria crosstalks
and tethering [
]. A close examination on the
association between Sig-1R and those proteins may
provide more insights in the future.
Sig-1R in HD
HD is an inherited disorder in an autosomal dominant
pattern due to an elongated CAG repeat in the Huntingtin
(Htt) gene, HTT, and is clinically characterized by
progressive retardation in motor, cognition and psychiatric states
]. HD mutation is associated with mitochondrial
dysfunction and apoptotic pathways. Inhibition of
mitochondrial function via the complex II inhibitor
3-nitropropionic acid (3NP) recapitulates HD-like
symptoms in animals [
]. Mitochondrial fractionation
revealed that Htt is present in the mitochondrial outer
membrane. Mutant Htt protein induced mitochondrial
permeability transition (MPT) accompanied by a
significant release of cytochrome c [
]. Overexpressing of Htt
proteins with 74 or 138 polyglutamine repeats induced
mitochondrial fragmentation under oxidative stress, in
which Htt 74 also caused cell death, reduction in ATP
levels, and interference on the dynamics of mitochondrial
]. Further, Htt could interact with Drp1
which controls mitochondrial fission, elevates Drp1
enzyme activities, and induces abnormal dynamics and
anterograde movements of mitochondria, thus leading to
disruption of synaptic functions [
Expression of N-terminal Htt proteins with expanded
polyglutamine activates ER stress, increases BiP protein
expression, and causes cell death in neuronal cells.
Compound that inhibits ER stress such as salubrinal could
rescue the cell death and eliminate protein aggregations
resulting from mutant Htt proteins [
]. A similar
approach was also used to investigate the relation between
Sig-1R and mutant Htt. Sig-1R expression is decreased in
mutant Htt protein-expressing cells [
]. Treatment of the
Sig-1R agonist PRE084 counteracted the effects caused by
mutant Htt by increasing cellular antioxidants, reducing
the ROS level, increasing NF-κB-p65, and activating
NF-κB signaling without changing mitochondrial Ca2+
concentration. A partial co-localization of Sig-1R with
aggregates of cytoplasmic mutant Htt was observed,
indicating that the Sig-1R may play some unknown roles in the
Htt aggregates such as being hijacked by the aggregates
with a loss of its function. Similar results were observed in
that Sig-1Rs translocated and colocalized with the mutant
Htt in the nucleus [
]. Although mitochondrial Ca2+
levels were not affected by mutant Htt proteins in this
model, another report indicated that the interaction of
type I IP3R with BiP was reduced in the HD mouse model
that was accompany by impaired Ca2+ releasing activity of
type I IP3R [
]. Moreover, a Sig-1R ligand, pridopidine
was found to improve motor function in a HD R6/2
mouse model. Pridopidine increased the expression of
neuroprotective factors, such as BDNF and DARPP32,
and reduced the size of Htt aggregates in HD mice. The
effect of pridopidine was abolished in the presence of
Sig1R antagonist in cellular model, implying that the Sig-1R
was involved in the neuroprotective functions of
]. Pridopidine activated neuronal plasticity and
survival pathways, and the Sig-1R may represent a major
regulator to increase the secretion of BDNF [
in a YAC128 transgenic HD mouse model, it was
demonstrated that pridopidine prevented the loss of medium
spiny neurons through Sig-1R in aging YAC128
cocultures. Pridopidine treatment also normalized the ER
Ca2+ levels in medium spiny neurons in the co-culture
]. Although the MAM region has not been
directly demonstrated to be involved in HD, the insightful
information mentioned in this section implies a relation
between Sig-1R’s function at MAM and HD may exist.
Sig-1R in ALS
The clinical hallmark of ALS is the presence of upper
and lower motor neuron dysfunction as seen in the
limbs that can further manifested as muscular atrophy
in other regions [
]. Mitochondrial pathology occurs
as an initial event in a mouse model of ALS [
motor nerve terminals from ALS patients contained
abnormal Ca2+ concentrations and increased
mitochondrial volumes [
]. Several risk factors have been
identified in ALS and demonstrated to be involved in
mitochondrial homeostasis, including SOD1 [
], TDP-43 [
], OPTN [
]. SOD1 scavenges free superoxide radicals
in the cells, and mutant SOD1 protein has been shown
to bind to the cytoplasmic face of mitochondria [
SOD1 mutant mouse model demonstrated
mitochondrial abnormalities, motor neuron death, and symptoms
and pathology similar to those observed in ALS [
Motor neurons expressing mutant SOD1 also showed
impairments in mitochondrial fusion in axons and soma,
dysregulsation of mitochondrial retrograde axonal
transport, and a reduction in the size of mitochondria [
Sig-1R proteins were reduced in the lumbar spinal
cord of ALS. They were also accumulated in enlarged
Cterminals and ER structures of alpha motor neurons.
The disrupted Sig-1R localization was also observed in
SOD1 transgenic mice [
]. A Sig-1R KO mouse model
showed muscle weakness and motor neuron loss, and
the inhibition of mitochondrial fission caused defect in
mitochondrial axonal transport and axonal degeneration
that were similar to that seen in Sig-1R deficiency
samples. Those defects can be restored by the Ca2+
scavenging and ER stress inhibition in motor neurons [
The collapse of the MAM (Fig. 1b) was demonstrated as
a common mechanism in Sig-1R- and SOD1-linked ALS
]. Watanabe et al. found that a homozygous
mutation p.L95fs of SIGMAR1 was identified in the
inherited juvenile ALS. The mutant variant of Sig-1R
showed reduced stability and was incapable of binding
to IP3R3s. The mutant SOD1 was also detected at the
MAM where the mutant was observed in neurons but
not in astrocytes or other cell types of the SOD1 mouse
model. Furthermore, deficiency of Sig-1Rs accelerated
the onset of SOD-1-mediated ALS in mouse model.
Deficiency of Sig-1R or accumulation of mutant SOD1
could induce the collapse of the MAM, leading to the
mislocalization of IP3R3s, the activation of calpain, and
the dysfunction of mitochondria. Administration of the
Sig-1R agonist PRE-084 restored the Sig-1R-IP3R3
interaction and prevented the Sig-1R aggregation [
TDP-43 was found to form hyper-phosphorylated,
ubiquitin-positive inclusions in ALS [
], and the ALS
disease-associated mutant TDP-43 exhibited greater
extent of mis-localization in mitochondria [
pathologic TDP-43 that perturbs the ER-mitochondrion
association was also observed [
]. The association of
Sig-1R and TDP-43 was documented in a study in which
a nonpolymorphic mutation in the 3′-untranslated
region of SIGMAR1 was identified in patients from the
frontotemporal lobar degeneration-motor neuron
disease (FTLD-MND) pedigree [
]. Brains of SIGMAR1
mutation carriers showed cytoplasmic inclusions of
TDP-43 or FUS. Overexpression of Sig-1R increased the
mislocalization of TDP-43 and FUS from the nucleus to
the cytoplasm while Sig-1R antagonists reduced the
cytoplasmic to nuclear TDP-43 ratio. The mutation of
the SIGMAR1 (p.E102Q) has also been found in the ALS
]. Overexpression of this mutant increased
mitochondrial damage, induced autophagic cell death,
and led to mislocalized TDP-43 [
]. The Sig-1R
was observed in the neuronal nuclear inclusions in
various neurodegenerative diseases, suggesting that the
Sig1R might move laterally between the nucleus and the
cytoplasm under certain conditions . Those findings
suggest a role of Sig-1R as well as the importance of
MAM integrity in ALS.
Sig-1R endogenous ligands in neurodegenerative diseases
In addition to the synthetic agonists and antagonists listed
above, the endogenous ligands of Sig-1Rs include the
steroids (progesterone, DHEA-sulfate and testosterone) [
], hallucinogen N,N-dimethyltryptamine (DMT) ,
] and monoglycosylated-ceramide
]. Progesterone was found to regulate free radical
metabolism in brain mitochondria and provides
neuroprotective and anti-inflammatory effects in the CNS [
]. A motor neuron degeneration mouse model showed
less pronounced abnormal mitochondria morphologies
after receiving progesterone , and progesterone also
regulate AD-like neuropathologies in female 3xTg-AD
]. Some steroids and progesterone are
synthesized at specific location of ER, and progesterone can
inhibit the dissociation of Sig-1R and BiP [
]. On the
contrary, pregnenolone sulfate also caused the dissociation
of an ankyrin B isoform from IP3R3, eliciting Ca2+
concentration and signaling [
]. DMT is a hallucinogen
found in human brain and is postulated to generate
endogenously under cellular stress [
]. Mice injected with
DMT showed hypermobility, but the effects were not
observed in the Sig-1R KO phenotype [
DMT binding to Sig-1R to modulate its actions.
Therefore, a model has been proposed that low concentration of
DMT dissociates Sig-1Rs from BiP, allowing Sig-1Rs to
regulate IP3R3s at the MAM. The Ca2+ signaling
increased from the ER into mitochondria as well as the ATP
production while higher concentrations of DMT induced
the translocation of Sig-1Rs from the MAM to other
cellular compartments, and inhibited ion channel’s activities
]. DMT producing enzyme also exhibited closed
proximity to the Sig-1R in the motor neurons, implying the
local synthesis of DMT in the wake of Sig-1R regulations
]. Later studies showed that DMT mitigated hypoxic
stress or modulated inflammatory responses via Sig-1R in
iPSC-derived cortical neurons or immune cells [
Sig-1Rs associate with simple sphingolipids such as
ceramides  which regulate mitochondrial functions such
as eliciting the release of proapoptotic factors from the
mitochondria, ROS production from mitochondria, and
lipid synthesis, and are also implicated in CNS pathologies
]. Identifying the putative endogenous ligands
excludes the Sig-1R as an orphan receptor, and the later
discovery on the chaperoning function via the IP3R3
redefines the pivotal role of the Sig-1R, nevertheless, the
subtle and coordinated actions/balances between Sig-1R
and its putative endogenous ligands remain to be clarified
to elucidate potential roles in the neurodegenerative
diseases or other psychiatric illnesses toward Sig-1Rs.
Conclusions and future perspective
The function of Sig-1R is activated when cells are under
stress. The Sig-1R chaperone protein exerts pluripotent
properties that can exist in the nuclear envelope, the
nucleoplasmic reticulum, the MAM, the ER, and
potentially the plasma membrane [
]. The main function of
Sig-1R is to regulate the Ca2+ gradient between ER and
mitochondria through the MAM. Recently, the crystal
structure of Sig-1R proposing a trimeric architecture
with a single transmembrane domain in each protomer,
with one side facing the ER lumen and the other side
facing the surface of the ER in cells [
]. This discovery
will accelerate the pace in understanding the ligand
binding state and other important cellular mechanisms
of Sig-1R. The Sig-1R has been proven to play certain
roles in many neurodegenerative diseases. Ligands of the
Sig-1R have also been shown to exhibit neuroprotective
properties, providing some potential promising therapies
in the future. It has been proposed that many aggregated
proteins related to neurodegenerative disease were
imported into mitochondria [
]. The regulatory
functions of the Sig-1R chaperone on mitochondria thus
deserve thorough investigations. The MAM, thus Sig-1Rs,
represents an important target in the treatment of
neurodegenerative diseases (Fig. 1). Whether Sig-1R
interactions with other MAM tethering proteins may relate to
those diseases remains to be fully investigated.
3NP: 3-nitropropionic acid; AD: Alzheimer’s disease; ALS: Amyotrophic lateral
sclerosis; APOE: Apolipoprotein E; APP: Amyloid precursor protein;
ARE: Antioxidant response element; Aβ: β-amyloid; BAF:
Barrier-toautointegration factor; CNS: Central nervous system; CYC1: Cytochrome C1;
DMT: N,N-dimethyltryptamine; ER: Endoplasmic reticulum;
FTLDMND: Frontotemporal lobar degeneration-motor neuron disease;
GalCer: Galactosylceramide; GM1: Monosialotetrahexosylganglioside;
H2O2: Hydrogen peroxide; HD: Huntington’s disease; HDAC: Histone
deacetylase; Htt: Huntingtin; IP3: Inositol 1,4,5-trisphosphate; IP3R: Inositol
1,4,5-trisphosphate receptor; IP3R3: Type 3 inositol 1,4,5-trisphosphate
receptor; IPAG: 1-(4-iodophenyl)-3-(2-adamantyl)guanidine;
MAM: Mitochondrion-associated ER membrane; MAOB: Monoamine oxidase
B; MPT: Mitochondrial permeability transition; mtDNA: mitochondrial DNA;
NF-κB: Nuclear factor κB; NO: Nitric oxide; NQO1: NADPH quinone
oxidoreductase 1; Nrf2: Nuclear factor erythroid 2-related factor 2;
OL: Oligodendrocyte; PD: Parkinson’s disease; PHB: Prohibitin;
PLC: Phospholipase C; PP2A: Protein phosphatase 2A; Prdx6: Peroxiredoxin 6;
PS1: Presenilin-1; PS2: Presenilin-2; PTPIP51: Protein tyrosine phosphatase
interacting protein 51; ROS: Reactive oxidative species; Sig-1R: Sigma-1
receptor; SLC25A11: Solute carrier family 25 member 11; SLC25A39: Solute
carrier family 25 member 39; Sp3: Pecific protein 3; StAR: Steroidogenic acute
regulatory protein; TBI: Traumatic brain injury; UPR: Unfolded protein
response; VAPB: Vesicle-associated membrane protein-associated protein B;
VDAC: Voltage-dependent anion channel; VDAC1: Voltage-dependent anion
channel 1; VDAC2: Voltage-dependent anion channel 2
We thank the Intramural Research Program of the National Institute on Drug
Abuse of the National Institutes of Health, the United States Department of
Health and Human Services, for the funding of this work.
This work was supported by the Intramural Research Program of the
National Institute on Drug Abuse, National Institutes of Health, United States
Department of Health and Human Services.
Availability of data and materials
All data in this review are already published and are available in public
T-YW and S-YAT wrote the manuscript. T-PS edited and finalized the manuscript.
All authors read and approved the final manuscript.
Ethics approval and consent to participate
Consent for publication
All authors have read the manuscript and agreed to the publication.
The authors declare that they have no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.
Submit your next manuscript to BioMed Central
and we will help you at every step:
Our selector tool helps you to find the most relevant journal
1. Hayashi T , Su TP . Regulating ankyrin dynamics: Roles of sigma-1 receptors . Proc Natl Acad Sci U S A . 2001 ; 98 : 491 - 6 .
2. Hayashi T , Su TP . Sigma-1 receptor chaperones at the ER-mitochondrion interface regulate Ca(2+) signaling and cell survival . Cell . 2007 ; 131 : 596 - 610 .
3. Srivats S , Balasuriya D , Pasche M , Vistal G , Edwardson JM , Taylor CW , et al. Sigma1 receptors inhibit store-operated Ca2+ entry by attenuating coupling of STIM1 to Orai1 . J Cell Biol . 2016 ; 213 : 65 - 79 .
4. Crottes D , Guizouarn H , Martin P , Borgese F , Soriani O. The sigma-1 receptor: a regulator of cancer cell electrical plasticity? Front Physiol . 2013 ; 4 : 175 .
5. Mavlyutov TA , Guo LW , Epstein ML , Ruoho AE . Role of the Sigma-1 receptor in Amyotrophic Lateral Sclerosis (ALS) . J Pharmacol Sci . 2015 ; 127 : 10 - 6 .
6. Hayashi T , Su TP . Sigma-1 receptors at galactosylceramide-enriched lipid microdomains regulate oligodendrocyte differentiation . Proc Natl Acad Sci U S A . 2004 ; 101 : 14949 - 54 .
7. Tsai SY , Pokrass MJ , Klauer NR , Nohara H , Su TP . Sigma-1 receptor regulates Tau phosphorylation and axon extension by shaping p35 turnover via myristic acid . Proc Natl Acad Sci U S A . 2015 ; 112 : 6742 - 7 .
8. Ciesielski J , Su TP , Tsai SY . Myristic acid hitchhiking on sigma-1 receptor to fend off neurodegeneration . Receptors Clin Investig . 2016 ; 3
9. Tsai SY , Hayashi T , Harvey BK , Wang Y , Wu WW , Shen RF , et al. Sigma-1 receptors regulate hippocampal dendritic spine formation via a free radicalsensitive mechanism involving Rac1xGTP pathway . Proc Natl Acad Sci U S A . 2009 ; 106 : 22468 - 73 .
10. Tsai SY , Pokrass MJ , Klauer NR , De Credico NE , Su TP . Sigma-1 receptor chaperones in neurodegenerative and psychiatric disorders . Expert Opin Ther Targets . 2014 ; 18 : 1461 - 76 .
11. Mori T , Hayashi T , Hayashi E , Su TP . Sigma-1 receptor chaperone at the ERmitochondrion interface mediates the mitochondrion-ER-nucleus signaling for cellular survival . PLoS One . 2013 ; 8 : e76941 .
12. Tsai SY , Chuang JY , Tsai MS , Wang XF , Xi ZX , Hung JJ , et al. Sigma-1 receptor mediates cocaine-induced transcriptional regulation by recruiting chromatin-remodeling factors at the nuclear envelope . Proc Natl Acad Sci U S A . 2015 ; 112 : E6562 - 70 .
13. Newmeyer DD , Ferguson-Miller S. Mitochondria : releasing power for life and unleashing the machineries of death . Cell . 2003 ; 112 : 481 - 90 .
14. Taanman JW . The mitochondrial genome: structure, transcription, translation and replication . Biochim Biophys Acta . 1999 ; 1410 : 103 - 23 .
15. Wang Z , Wu M. An integrated phylogenomic approach toward pinpointing the origin of mitochondria . Sci Rep . 2015 ; 5 : 7949 .
16. Kuhlbrandt W. Structure and function of mitochondrial membrane protein complexes . BMC Biol . 2015 ; 13 : 89 .
17. Mishra P , Chan DC . Metabolic regulation of mitochondrial dynamics . J Cell Biol . 2016 ; 212 : 379 - 87 .
18. Youle RJ , van der Bliek AM. Mitochondrial fission, fusion, and stress . Science . 2012 ; 337 : 1062 - 5 .
19. Carelli V , Chan DC . Mitochondrial DNA: impacting central and peripheral nervous systems . Neuron . 2014 ; 84 : 1126 - 42 .
20. Duchen MR . Mitochondria and calcium: from cell signalling to cell death . J Physiol . 2000 ; 529 (Pt 1): 57 - 68 .
21. Murphy MP . How mitochondria produce reactive oxygen species . Biochem J . 2009 ; 417 : 1 - 13 .
22. Wang C , Youle RJ . The role of mitochondria in apoptosis* . Annu Rev Genet . 2009 ; 43 : 95 - 118 .
23. Federico A , Cardaioli E , Da Pozzo P , Formichi P , Gallus GN , Radi E . Mitochondria, oxidative stress and neurodegeneration . J Neurol Sci . 2012 ; 322 : 254 - 62 .
24. Chinnery PF . Mitochondrial Disorders Overview . In Pagon RA , Adam MP , Ardinger HH , et al., editors. GeneReviews(R) . Seattle (WA): University of Washington, Seattle; 1993 .
25. Copeland DE , Dalton AJ . An association between mitochondria and the endoplasmic reticulum in cells of the pseudobranch gland of a teleost . J Biophys Biochem Cytol . 1959 ; 5 : 393 - 6 .
26. Rusinol AE , Cui Z , Chen MH , Vance JE . A unique mitochondria-associated membrane fraction from rat liver has a high capacity for lipid synthesis and contains pre-Golgi secretory proteins including nascent lipoproteins . J Biol Chem . 1994 ; 269 : 27494 - 502 .
27. Stone SJ , Vance JE . Phosphatidylserine synthase-1 and -2 are localized to mitochondria-associated membranes . J Biol Chem . 2000 ; 275 : 34534 - 40 .
28. Fujimoto M , Hayashi T . New insights into the role of mitochondriaassociated endoplasmic reticulum membrane . Int Rev Cell Mol Biol . 2011 ; 292 : 73 - 117 .
29. Vance JE. MAM (mitochondria-associated membranes) in mammalian cells: lipids and beyond . Biochim Biophys Acta . 1841 ; 2014 : 595 - 609 .
30. Rizzuto R , Brini M , Murgia M , Pozzan T. Microdomains with high Ca2+ close to IP3-sensitive channels that are sensed by neighboring mitochondria . Science . 1993 ; 262 : 744 - 7 .
31. Rizzuto R , Duchen MR , Pozzan T. Flirting in little space: the ER/mitochondria Ca2+ liaison . Sci STKE . 2004 ; 2004 : re1 .
32. Mendes CC , Gomes DA , Thompson M , Souto NC , Goes TS , Goes AM , et al. The type III inositol 1 , 4 ,5 -trisphosphate receptor preferentially transmits apoptotic Ca2+ signals into mitochondria . J Biol Chem . 2005 ; 280 : 40892 - 900 .
33. Vance JE . Phospholipid synthesis in a membrane fraction associated with mitochondria . J Biol Chem . 1990 ; 265 : 7248 - 56 .
34. Csordas G , Varnai P , Golenar T , Roy S , Purkins G , Schneider TG , et al. Imaging interorganelle contacts and local calcium dynamics at the ER-mitochondrial interface . Mol Cell . 2010 ; 39 : 121 - 32 .
35. Decuypere JP , Monaco G , Bultynck G , Missiaen L , De Smedt H , Parys JB . The IP(3) receptor-mitochondria connection in apoptosis and autophagy . Biochim Biophys Acta . 1813 ; 2011 : 1003 - 13 .
36. Shioda N , Ishikawa K , Tagashira H , Ishizuka T , Yawo H , Fukunaga K. Expression of a truncated form of the endoplasmic reticulum chaperone protein, sigma1 receptor, promotes mitochondrial energy depletion and apoptosis . J Biol Chem . 2012 ; 287 : 23318 - 31 .
37. Tagashira H , Shinoda Y , Shioda N , Fukunaga K. Methyl pyruvate rescues mitochondrial damage caused by SIGMAR1 mutation related to amyotrophic lateral sclerosis . Biochim Biophys Acta . 1840 ; 2014 : 3320 - 34 .
38. Natsvlishvili N , Goguadze N , Zhuravliova E , Mikeladze D . Sigma-1 receptor directly interacts with Rac1-GTPase in the brain mitochondria . BMC Biochem . 2015 ; 16 : 11 .
39. Tagashira H , Zhang C , Lu YM , Hasegawa H , Kanai H , Han F , et al. Stimulation of sigma1-receptor restores abnormal mitochondrial Ca(2)(+) mobilization and ATP production following cardiac hypertrophy . Biochim Biophys Acta . 1830 ; 2013 : 3082 - 94 .
40. Cory S , Huang DC , Adams JM . The Bcl-2 family: roles in cell survival and oncogenesis . Oncogene . 2003 ; 22 : 8590 - 607 .
41. Meunier J , Hayashi T . Sigma -1 receptors regulate Bcl-2 expression by reactive oxygen species-dependent transcriptional regulation of nuclear factor kappaB . J Pharmacol Exp Ther . 2010 ; 332 : 388 - 97 .
42. Yang S , Bhardwaj A , Cheng J , Alkayed NJ , Hurn PD , Kirsch JR . Sigma receptor agonists provide neuroprotection in vitro by preserving bcl-2 . Anesth Analg . 2007 ; 104 : 1179 - 84 . tables of contents
43. Ha Y , Shanmugam AK , Markand S , Zorrilla E , Ganapathy V , Smith SB . Sigma receptor 1 modulates ER stress and Bcl2 in murine retina . Cell Tissue Res . 2014 ; 356 : 15 - 27 .
44. Tchedre KT , Yorio T. sigma -1 receptors protect RGC-5 cells from apoptosis by regulating intracellular calcium, Bax levels, and caspase-3 activation . Invest Ophthalmol Vis Sci . 2008 ; 49 : 2577 - 88 .
45. Spruce BA , Campbell LA , McTavish N , Cooper MA , Appleyard MV , O'Neill M , et al. Small molecule antagonists of the sigma-1 receptor cause selective release of the death program in tumor and self-reliant cells and inhibit tumor growth in vitro and in vivo . Cancer Res . 2004 ; 64 : 4875 - 86 .
46. Achison M , Boylan MT , Hupp TR , Spruce BA . HIF-1alpha contributes to tumour-selective killing by the sigma receptor antagonist rimcazole . Oncogene . 2007 ; 26 : 1137 - 46 .
47. Shen K , Zhang Y , Lv X , Chen X , Zhou R , Nguyen LK , et al. Molecular Mechanisms Involving Sigma-1 Receptor in Cell Apoptosis of BV-2 Microglial Cells Induced by Methamphetamine . CNS Neurol Disord Drug Targets . 2016 ; 15 : 857 - 65 .
48. Liu CY , Kaufman RJ . The unfolded protein response . J Cell Sci . 2003 ; 116 : 1861 - 2 .
49. Bravo R , Vicencio JM , Parra V , Troncoso R , Munoz JP , Bui M , et al. Increased ER-mitochondrial coupling promotes mitochondrial respiration and bioenergetics during early phases of ER stress . J Cell Sci . 2011 ; 124 : 2143 - 52 .
50. Bravo R , Gutierrez T , Paredes F , Gatica D , Rodriguez AE , Pedrozo Z , et al. Endoplasmic reticulum: ER stress regulates mitochondrial bioenergetics . Int J Biochem Cell Biol . 2012 ; 44 : 16 - 20 .
51. Tsai SY , Rothman RK , Su TP . Insights into the Sigma-1 receptor chaperone's cellular functions: a microarray report . Synapse . 2012 ; 66 : 42 - 51 .
52. Ha Y , Dun Y , Thangaraju M , Duplantier J , Dong Z , Liu K , et al. Sigma receptor 1 modulates endoplasmic reticulum stress in retinal neurons . Invest Ophthalmol Vis Sci . 2011 ; 52 : 527 - 40 .
53. Mitsuda T , Omi T , Tanimukai H , Sakagami Y , Tagami S , Okochi M , et al. Sigma1Rs are upregulated via PERK/eIF2alpha/ATF4 pathway and execute protective function in ER stress . Biochem Biophys Res Commun . 2011 ; 415 : 519 - 25 .
54. Omi T , Tanimukai H , Kanayama D , Sakagami Y , Tagami S , Okochi M , et al. Fluvoxamine alleviates ER stress via induction of Sigma-1 receptor . Cell Death Dis . 2014 ; 5 : e1332 .
55. Uttara B , Singh AV , Zamboni P , Mahajan RT . Oxidative stress and neurodegenerative diseases: a review of upstream and downstream antioxidant therapeutic options . Curr Neuropharmacol . 2009 ; 7 : 65 - 74 .
56. Meunier J , Ieni J , Maurice T. The anti-amnesic and neuroprotective effects of donepezil against amyloid beta25-35 peptide-induced toxicity in mice involve an interaction with the sigma1 receptor . Br J Pharmacol . 2006 ; 149 : 998 - 1012 .
57. Dong H , Ma Y , Ren Z , Xu B , Zhang Y , Chen J , et al. Sigma-1 Receptor Modulates Neuroinflammation After Traumatic Brain Injury . Cell Mol Neurobiol . 2016 ; 36 : 639 - 45 .
58. Wang L , Eldred JA , Sidaway P , Sanderson J , Smith AJ , Bowater RP , et al. Sigma 1 receptor stimulation protects against oxidative damage through suppression of the ER stress responses in the human lens . Mech Ageing Dev . 2012 ; 133 : 665 - 74 .
59. Pal A , Fontanilla D , Gopalakrishnan A , Chae YK , Markley JL , Ruoho AE . The sigma-1 receptor protects against cellular oxidative stress and activates antioxidant response elements . Eur J Pharmacol . 2012 ; 682 : 12 - 20 .
60. Johnson JA , Johnson DA , Kraft AD , Calkins MJ , Jakel RJ , Vargas MR , et al. The Nrf2-ARE pathway: an indicator and modulator of oxidative stress in neurodegeneration . Ann N Y Acad Sci . 2008 ; 1147 : 61 - 9 .
61. Wang J , Shanmugam A , Markand S , Zorrilla E , Ganapathy V , Smith SB . Sigma 1 receptor regulates the oxidative stress response in primary retinal Muller glial cells via NRF2 signaling and system xc(−), the Na(+)-independent glutamate-cystine exchanger . Free Radic Biol Med . 2015 ; 86 : 25 - 36 .
62. Dinkova-Kostova AT , Abramov AY . The emerging role of Nrf2 in mitochondrial function . Free Radic Biol Med . 2015 ; 88 : 179 - 88 .
63. Strom J , Xu B , Tian X , Chen QM . Nrf2 protects mitochondrial decay by oxidative stress . FASEB J . 2016 ; 30 : 66 - 80 .
64. Su TC , Lin SH , Lee PT , Yeh SH , Hsieh TH , Chou SY , et al. The sigma-1 receptor-zinc finger protein 179 pathway protects against hydrogen peroxide-induced cell injury . Neuropharmacology . 2016 ; 105 : 1 - 9 .
65. He C , Klionsky DJ . Regulation mechanisms and signaling pathways of autophagy . Annu Rev Genet . 2009 ; 43 : 67 - 93 .
66. Lee J , Giordano S , Zhang J . Autophagy, mitochondria and oxidative stress: cross-talk and redox signalling . Biochem J . 2012 ; 441 : 523 - 40 .
67. Cardenas C , Miller RA , Smith I , Bui T , Molgo J , Muller M , et al. Essential regulation of cell bioenergetics by constitutive InsP3 receptor Ca2+ transfer to mitochondria . Cell . 2010 ; 142 : 270 - 83 .
68. Geisler S , Holmstrom KM , Skujat D , Fiesel FC , Rothfuss OC , Kahle PJ , et al. PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/ SQSTM1 . Nat Cell Biol . 2010 ; 12 : 119 - 31 .
69. Hamasaki M , Furuta N , Matsuda A , Nezu A , Yamamoto A , Fujita N , et al. Autophagosomes form at ER-mitochondria contact sites . Nature . 2013 ; 495 : 389 - 93 .
70. Schrock JM , Spino CM , Longen CG , Stabler SM , Marino JC , Pasternak GW , et al. Sequential cytoprotective responses to Sigma1 ligand-induced endoplasmic reticulum stress . Mol Pharmacol . 2013 ; 84 : 751 - 62 .
71. Vollrath JT , Sechi A , Dreser A , Katona I , Wiemuth D , Vervoorts J , et al. Loss of function of the ALS protein SigR1 leads to ER pathology associated with defective autophagy and lipid raft disturbances . Cell Death Dis . 2014 ; 5 : e1290 .
72. Miki Y , Mori F , Kon T , Tanji K , Toyoshima Y , Yoshida M , et al. Accumulation of the sigma-1 receptor is common to neuronal nuclear inclusions in various neurodegenerative diseases . Neuropathology . 2014 ; 34 : 148 - 58 .
73. Cao L , Walker MP , Vaidya NK , Fu M , Kumar S , Kumar A . Cocaine-Mediated Autophagy in Astrocytes Involves Sigma 1 Receptor, PI3K, mTOR, Atg5/7, Beclin-1 and Induces Type II Programed Cell Death . Mol Neurobiol . 2016 ; 53 : 4417 - 30 .
74. Kasahara R , Yamamoto N , Suzuki K , Sobue K. The sigma1 receptor regulates accumulation of GM1 ganglioside-enriched autophagosomes in astrocytes . Neuroscience . 2017 ; 340 : 176 - 87 .
75. MacVicar TD , Mannack LV , Lees RM , Lane JD . Targeted siRNA Screens Identify ER-to-Mitochondrial Calcium Exchange in Autophagy and Mitophagy Responses in RPE1 Cells . Int J Mol Sci . 2015 ; 16 : 13356 - 80 .
76. Hayashi T , Fujimoto M . Detergent-resistant microdomains determine the localization of sigma-1 receptors to the endoplasmic reticulummitochondria junction . Mol Pharmacol . 2010 ; 77 : 517 - 28 .
77. Marriott KS , Prasad M , Thapliyal V , Bose HS . Sigma-1 receptor at the mitochondrial-associated endoplasmic reticulum membrane is responsible for mitochondrial metabolic regulation . J Pharmacol Exp Ther . 2012 ; 343 : 578 - 86 .
78. Maurya SR , Mahalakshmi R . VDAC-2: Mitochondrial outer membrane regulator masquerading as a channel? FEBS J . 2016 ; 283 : 1831 - 6 .
79. Naghdi S , Hajnoczky G . VDAC2 -specific cellular functions and the underlying structure . Biochim Biophys Acta . 1863 ; 2016 : 2503 - 14 .
80. Prasad M , Kaur J , Pawlak KJ , Bose M , Whittal RM , Bose HS . Mitochondriaassociated endoplasmic reticulum membrane (MAM) regulates steroidogenic activity via steroidogenic acute regulatory protein (StAR)- voltage-dependent anion channel 2 (VDAC2) interaction . J Biol Chem . 2015 ; 290 : 2604 - 16 .
81. Schmitt T , Ogris C , Sonnhammer EL. FunCoup 3 . 0: database of genomewide functional coupling networks . Nucleic Acids Res . 2014 ; 42 : D380 - 8 .
82. Su TP , Su TC , Nakamura Y , Tsai SY . The Sigma-1 Receptor as a Pluripotent Modulator in Living Systems . Trends Pharmacol Sci . 2016 ; 37 : 262 - 78 .
83. Sun J , Trumpower BL . Superoxide anion generation by the cytochrome bc1 complex . Arch Biochem Biophys . 2003 ; 419 : 198 - 206 .
84. Yu Z , Poppe JL , Wang X . Mitochondrial mechanisms of neuroglobin's neuroprotection . Oxidative Med Cell Longev . 2013 ; 2013 : 756989 .
85. Merkwirth C , Langer T. Prohibitin function within mitochondria: essential roles for cell proliferation and cristae morphogenesis . Biochim Biophys Acta . 2009 ; 1793 : 27 - 32 .
86. Palmieri F. The mitochondrial transporter family (SLC25): physiological and pathological implications . Pflugers Arch . 2004 ; 447 : 689 - 709 .
87. Wilkins HM , Kirchhof D , Manning E , Joseph JW , Linseman DA . Mitochondrial glutathione transport is a key determinant of neuronal susceptibility to oxidative and nitrosative stress . J Biol Chem . 2013 ; 288 : 5091 - 101 .
88. Kann O , Kovacs R . Mitochondria and neuronal activity . Am J Physiol Cell Physiol . 2007 ; 292 : C641 - 57 .
89. Lin MT , Beal MF . Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases . Nature . 2006 ; 443 : 787 - 95 .
90. Johri A , Beal MF . Mitochondrial dysfunction in neurodegenerative diseases . J Pharmacol Exp Ther . 2012 ; 342 : 619 - 30 .
91. Paillusson S , Stoica R , Gomez-Suaga P , Lau DH , Mueller S , Miller T , et al. There's Something Wrong with my MAM; the ER-Mitochondria Axis and Neurodegenerative Diseases . Trends Neurosci . 2016 ; 39 : 146 - 57 .
92. van Vliet AR , Verfaillie T , Agostinis P . New functions of mitochondria associated membranes in cellular signaling . Biochim Biophys Acta . 1843 ; 2014 : 2253 - 62 .
93. Rodriguez-Arribas M , Yakhine-Diop SM , Pedro JM , Gomez-Suaga P , GomezSanchez R , Martinez-Chacon G , et al. Mitochondria-Associated Membranes (MAMs): Overview and Its Role in Parkinson's Disease . Mol Neurobiol . 2016 ; 54 : 6287 - 6303 .
94. Nguyen L , Lucke-Wold BP , Mookerjee SA , Cavendish JZ , Robson MJ , Scandinaro AL , et al. Role of sigma-1 receptors in neurodegenerative diseases . J Pharmacol Sci . 2015 ; 127 : 17 - 29 .
95. Nguyen L , Lucke-Wold BP , Mookerjee S , Kaushal N , Matsumoto RR . Sigma-1 Receptors and Neurodegenerative Diseases: Towards a Hypothesis of Sigma-1 Receptors as Amplifiers of Neurodegeneration and Neuroprotection . Adv Exp Med Biol . 2017 ; 964 : 133 - 52 .
96. Jin JL , Fang M , Zhao YX , Liu XY . Roles of sigma-1 receptors in Alzheimer's disease . Int J Clin Exp Med . 2015 ; 8 : 4808 - 20 .
97. Mishina M , Ishiwata K , Ishii K , Kitamura S , Kimura Y , Kawamura K , et al. Function of sigma1 receptors in Parkinson's disease . Acta Neurol Scand . 2005 ; 112 : 103 - 7 .
98. Hyrskyluoto A , Pulli I , Tornqvist K , Ho TH , Korhonen L , Lindholm D . Sigma-1 receptor agonist PRE084 is protective against mutant huntingtin-induced cell degeneration: involvement of calpastatin and the NF-kappaB pathway . Cell Death Dis . 2013 ; 4 : e646 .
99. Ruscher K , Wieloch T. The involvement of the sigma-1 receptor in neurodegeneration and neurorestoration . J Pharmacol Sci . 2015 ; 127 : 30 - 5 .
100. Katnik C , Guerrero WR , Pennypacker KR , Herrera Y , Cuevas J. Sigma -1 receptor activation prevents intracellular calcium dysregulation in cortical neurons during in vitro ischemia . J Pharmacol Exp Ther . 2006 ; 319 : 1355 - 65 .
101. Romero L , Zamanillo D , Nadal X , Sanchez-Arroyos R , Rivera-Arconada I , Dordal A , et al. Pharmacological properties of S1RA, a new sigma-1 receptor antagonist that inhibits neuropathic pain and activity-induced spinal sensitization . Br J Pharmacol . 2012 ; 166 : 2289 - 306 .
102. Hayashi T , Su TP . Sigma-1 receptor ligands: potential in the treatment of neuropsychiatric disorders . CNS Drugs . 2004 ; 18 : 269 - 84 .
103. Sha S , Hong J , Qu WJ , Lu ZH , Li L , Yu WF , et al. Sex-related neurogenesis decrease in hippocampal dentate gyrus with depressivelike behaviors in sigma-1 receptor knockout mice . Eur Neuropsychopharmacol . 2015 ; 25 : 1275 - 86 .
104. Langa F , Codony X , Tovar V , Lavado A , Gimenez E , Cozar P , et al. Generation and phenotypic analysis of sigma receptor type I (sigma 1) knockout mice . Eur J Neurosci . 2003 ; 18 : 2188 - 96 .
105. Sabino V , Cottone P , Parylak SL , Steardo L , Zorrilla EP . Sigma-1 receptor knockout mice display a depressive-like phenotype . Behav Brain Res . 2009 ; 198 : 472 - 6 .
106. Devi L , Prabhu BM , Galati DF , Avadhani NG , Anandatheerthavarada HK . Accumulation of amyloid precursor protein in the mitochondrial import channels of human Alzheimer's disease brain is associated with mitochondrial dysfunction . J Neurosci . 2006 ; 26 : 9057 - 68 .
107. Caspersen C , Wang N , Yao J , Sosunov A , Chen X , Lustbader JW , et al. Mitochondrial Abeta: a potential focal point for neuronal metabolic dysfunction in Alzheimer's disease . FASEB J . 2005 ; 19 : 2040 - 1 .
108. Manczak M , Anekonda TS , Henson E , Park BS , Quinn J , Reddy PH . Mitochondria are a direct site of A beta accumulation in Alzheimer's disease neurons: implications for free radical generation and oxidative damage in disease progression . Hum Mol Genet . 2006 ; 15 : 1437 - 49 .
109. Yan SD , Stern DM . Mitochondrial dysfunction and Alzheimer's disease: role of amyloid-beta peptide alcohol dehydrogenase (ABAD) . Int J Exp Pathol . 2005 ; 86 : 161 - 71 .
110. Zhao XL , Wang WA , Tan JX , Huang JK , Zhang X , Zhang BZ , et al. Expression of beta-amyloid induced age-dependent presynaptic and axonal changes in Drosophila . J Neurosci . 2010 ; 30 : 1512 - 22 .
111. Schreiner B , Hedskog L , Wiehager B , Ankarcrona M . Amyloid-beta peptides are generated in mitochondria-associated endoplasmic reticulum membranes . J Alzheimers Dis . 2015 ; 43 : 369 - 74 .
112. Behensky AA , Yasny IE , Shuster AM , Seredenin SB , Petrov AV , Cuevas J . Afobazole activation of sigma-1 receptors modulates neuronal responses to amyloid-beta25-35 . J Pharmacol Exp Ther . 2013 ; 347 : 468 - 77 .
113. Hedskog L , Pinho CM , Filadi R , Ronnback A , Hertwig L , Wiehager B , et al. Modulation of the endoplasmic reticulum-mitochondria interface in Alzheimer's disease and related models . Proc Natl Acad Sci U S A . 2013 ; 110 : 7916 - 21 .
114. Toyohara J , Sakata M , Ishiwata K. Imaging of sigma1 receptors in the human brain using PET and [11C] SA4503 . Cent Nerv Syst Agents Med Chem . 2009 ; 9 : 190 - 6 .
115. Barbero-Camps E , Fernandez A , Baulies A , Martinez L , Fernandez-Checa JC , Colell A . Endoplasmic reticulum stress mediates amyloid beta neurotoxicity via mitochondrial cholesterol trafficking . Am J Pathol . 2014 ; 184 : 2066 - 81 .
116. Giorgi C , Ito K , Lin HK , Santangelo C , Wieckowski MR , Lebiedzinska M , et al. PML regulates apoptosis at endoplasmic reticulum by modulating calcium release . Science . 2010 ; 330 : 1247 - 51 .
117. Placido AI , Pereira CM , Correira SC , Carvalho C , Oliveira CR , Moreira PI . Phosphatase 2A Inhibition Affects Endoplasmic Reticulum and Mitochondria Homeostasis Via Cytoskeletal Alterations in Brain Endothelial Cells . Mol Neurobiol . 2017 ; 54 : 154 - 68 .
118. Huang Y , Zheng L , Halliday G , Dobson-Stone C , Wang Y , Tang HD , et al. Genetic polymorphisms in sigma-1 receptor and apolipoprotein E interact to influence the severity of Alzheimer's disease . Curr Alzheimer Res . 2011 ; 8 : 765 - 70 .
119. Tambini MD , Pera M , Kanter E , Yang H , Guardia-Laguarta C , Holtzman D , et al. ApoE4 upregulates the activity of mitochondria-associated ER membranes . EMBO Rep . 2016 ; 17 : 27 - 36 .
120. Area-Gomez E , de Groof AJ , Boldogh I , Bird TD , Gibson GE , Koehler CM , et al. Presenilins are enriched in endoplasmic reticulum membranes associated with mitochondria . Am J Pathol . 2009 ; 175 : 1810 - 6 .
121. Area-Gomez E , Del Carmen Lara Castillo M , Tambini MD , Guardia-Laguarta C , de Groof AJ , Madra M , et al. Upregulated function of mitochondriaassociated ER membranes in Alzheimer disease . EMBO J . 2012 ; 31 : 4106 - 23 .
122. Zampese E , Fasolato C , Kipanyula MJ , Bortolozzi M , Pozzan T , Pizzo P . Presenilin 2 modulates endoplasmic reticulum (ER)-mitochondria interactions and Ca2+ cross-talk . Proc Natl Acad Sci U S A . 2011 ; 108 : 2777 - 82 .
123. Sepulveda-Falla D , Barrera-Ocampo A , Hagel C , Korwitz A , Vinueza-Veloz MF , Zhou K , et al. Familial Alzheimer's disease-associated presenilin-1 alters cerebellar activity and calcium homeostasis . J Clin Invest . 2014 ; 124 : 1552 - 67 .
124. Manczak M , Reddy PH . Abnormal interaction between the mitochondrial fission protein Drp1 and hyperphosphorylated tau in Alzheimer's disease neurons: implications for mitochondrial dysfunction and neuronal damage . Hum Mol Genet . 2012 ; 21 : 2538 - 47 .
125. Quintanilla RA , Matthews-Roberson TA , Dolan PJ , Johnson GV . Caspasecleaved tau expression induces mitochondrial dysfunction in immortalized cortical neurons: implications for the pathogenesis of Alzheimer disease . J Biol Chem . 2009 ; 284 : 18754 - 66 .
126. Dauer W , Przedborski S. Parkinson's disease: mechanisms and models . Neuron . 2003 ; 39 : 889 - 909 .
127. Devi L , Raghavendran V , Prabhu BM , Avadhani NG , Anandatheerthavarada HK . Mitochondrial import and accumulation of alpha-synuclein impair complex I in human dopaminergic neuronal cultures and Parkinson disease brain . J Biol Chem . 2008 ; 283 : 9089 - 100 .
128. Parihar MS , Parihar A , Fujita M , Hashimoto M , Ghafourifar P . Mitochondrial association of alpha-synuclein causes oxidative stress . Cell Mol Life Sci . 2008 ; 65 : 1272 - 84 .
129. Deng H , Dodson MW , Huang H , Guo M. The Parkinson's disease genes pink1 and parkin promote mitochondrial fission and/or inhibit fusion in Drosophila . Proc Natl Acad Sci U S A . 2008 ; 105 : 14503 - 8 .
130. Clark IE , Dodson MW , Jiang C , Cao JH , Huh JR , Seol JH , et al. Drosophila pink1 is required for mitochondrial function and interacts genetically with parkin . Nature . 2006 ; 441 : 1162 - 6 .
131. Park J , Lee SB , Lee S , Kim Y , Song S , Kim S , et al. Mitochondrial dysfunction in Drosophila PINK1 mutants is complemented by parkin . Nature . 2006 ; 441 : 1157 - 61 .
132. Zhang L , Shimoji M , Thomas B , Moore DJ , Yu SW , Marupudi NI , et al. Mitochondrial localization of the Parkinson's disease related protein DJ-1: implications for pathogenesis . Hum Mol Genet . 2005 ; 14 : 2063 - 73 .
133. Hayashi T , Ishimori C , Takahashi-Niki K , Taira T , Kim YC , Maita H , et al. DJ-1 binds to mitochondrial complex I and maintains its activity . Biochem Biophys Res Commun . 2009 ; 390 : 667 - 72 .
134. Junn E , Jang WH , Zhao X , Jeong BS , Mouradian MM . Mitochondrial localization of DJ-1 leads to enhanced neuroprotection . J Neurosci Res . 2009 ; 87 : 123 - 9 .
135. Wang X , Yan MH , Fujioka H , Liu J , Wilson-Delfosse A , Chen SG , et al. LRRK2 regulates mitochondrial dynamics and function through direct interaction with DLP1 . Hum Mol Genet . 2012 ; 21 : 1931 - 44 .
136. Mori T , Hayashi T , Su TP . Compromising sigma-1 receptors at the endoplasmic reticulum render cytotoxicity to physiologically relevant concentrations of dopamine in a nuclear factor-kappaB/Bcl-2-dependent mechanism: potential relevance to Parkinson's disease . J Pharmacol Exp Ther . 2012 ; 341 : 663 - 71 .
137. Cali T , Ottolini D , Negro A , Brini M. alpha-Synuclein controls mitochondrial calcium homeostasis by enhancing endoplasmic reticulum-mitochondria interactions . J Biol Chem . 2012 ; 287 : 17914 - 29 .
138. Guardia-Laguarta C , Area-Gomez E , Rub C , Liu Y , Magrane J , Becker D , et al. alpha-Synuclein is localized to mitochondria-associated ER membranes . J Neurosci . 2014 ; 34 : 249 - 59 .
139. Paillusson S , Gomez-Suaga P , Stoica R , Little D , Gissen P , Devine MJ , et al. alpha-Synuclein binds to the ER-mitochondria tethering protein VAPB to disrupt Ca2+ homeostasis and mitochondrial ATP production . Acta Neuropathol . 2017 ; 134 : 129 - 49 .
140. Hao LY , Giasson BI , Bonini NM . DJ-1 is critical for mitochondrial function and rescues PINK1 loss of function . Proc Natl Acad Sci U S A . 2010 ; 107 : 9747 - 52 .
141. Cali T , Ottolini D , Negro A , Brini M. Enhanced parkin levels favor ERmitochondria crosstalk and guarantee Ca(2+) transfer to sustain cell bioenergetics . Biochim Biophys Acta . 1832 ; 2013 : 495 - 508 .
142. Ottolini D , Cali T , Negro A , Brini M. The Parkinson disease-related protein DJ1 counteracts mitochondrial impairment induced by the tumour suppressor protein p53 by enhancing endoplasmic reticulum-mitochondria tethering . Hum Mol Genet . 2013 ; 22 : 2152 - 68 .
143. Roos RA . Huntington's disease: a clinical review . Orphanet J Rare Dis . 2010 ; 5 : 40 .
144. Brouillet E , Conde F , Beal MF , Hantraye P. Replicating Huntington's disease phenotype in experimental animals . Prog Neurobiol . 1999 ; 59 : 427 - 68 .
145. Choo YS , Johnson GV , MacDonald M , Detloff PJ , Lesort M. Mutant huntingtin directly increases susceptibility of mitochondria to the calciuminduced permeability transition and cytochrome c release . Hum Mol Genet . 2004 ; 13 : 1407 - 20 .
146. Wang H , Lim PJ , Karbowski M , Monteiro MJ . Effects of overexpression of huntingtin proteins on mitochondrial integrity . Hum Mol Genet . 2009 ; 18 : 737 - 52 .
147. Shirendeb UP , Calkins MJ , Manczak M , Anekonda V , Dufour B , McBride JL , et al. Mutant huntingtin's interaction with mitochondrial protein Drp1 impairs mitochondrial biogenesis and causes defective axonal transport and synaptic degeneration in Huntington's disease . Hum Mol Genet . 2012 ; 21 : 406 - 20 .
148. Reijonen S , Putkonen N , Norremolle A , Lindholm D , Korhonen L. Inhibition of endoplasmic reticulum stress counteracts neuronal cell death and protein aggregation caused by N-terminal mutant huntingtin proteins . Exp Cell Res . 2008 ; 314 : 950 - 60 .
149. Miki Y , Tanji K , Mori F , Wakabayashi K. Sigma-1 receptor is involved in degradation of intranuclear inclusions in a cellular model of Huntington's disease . Neurobiol Dis . 2015 ; 74 : 25 - 31 .
150. Higo T , Hamada K , Hisatsune C , Nukina N , Hashikawa T , Hattori M , et al. Mechanism of ER stress-induced brain damage by IP(3) receptor . Neuron. 2010 ; 68 : 865 - 78 .
151. Squitieri F , Di Pardo A , Favellato M , Amico E , Maglione V , Frati L . Pridopidine, a dopamine stabilizer, improves motor performance and shows neuroprotective effects in Huntington disease R6/2 mouse model . J Cell Mol Med . 2015 ; 19 : 2540 - 8 .
152. Geva M , Kusko R , Soares H , Fowler KD , Birnberg T , Barash S , et al. Pridopidine activates neuroprotective pathways impaired in Huntington Disease . Hum Mol Genet . 2016 ; 25 : 3975 - 87 .
153. Ryskamp D , Wu J , Geva M , Kusko R , Grossman I , Hayden M , et al. The sigma1 receptor mediates the beneficial effects of pridopidine in a mouse model of Huntington disease . Neurobiol Dis . 2017 ; 97 : 46 - 59 .
154. Kiernan MC , Vucic S , Cheah BC , Turner MR , Eisen A , Hardiman O , et al. Amyotrophic lateral sclerosis . Lancet . 2011 ; 377 : 942 - 55 .
155. Borthwick GM , Johnson MA , Ince PG , Shaw PJ , Turnbull DM . Mitochondrial enzyme activity in amyotrophic lateral sclerosis: implications for the role of mitochondria in neuronal cell death . Ann Neurol . 1999 ; 46 : 787 - 90 .
156. Siklos L , Engelhardt J , Harati Y , Smith RG , Joo F , Appel SH . Ultrastructural evidence for altered calcium in motor nerve terminals in amyotropic lateral sclerosis . Ann Neurol . 1996 ; 39 : 203 - 16 .
157. Kong J , Xu Z . Massive mitochondrial degeneration in motor neurons triggers the onset of amyotrophic lateral sclerosis in mice expressing a mutant SOD1 . J Neurosci . 1998 ; 18 : 3241 - 50 .
158. Vande Velde C , Miller TM , Cashman NR , Cleveland DW . Selective association of misfolded ALS-linked mutant SOD1 with the cytoplasmic face of mitochondria . Proc Natl Acad Sci U S A . 2008 ; 105 : 4022 - 7 .
159. Magrane J , Sahawneh MA , Przedborski S , Estevez AG , Manfredi G . Mitochondrial dynamics and bioenergetic dysfunction is associated with synaptic alterations in mutant SOD1 motor neurons . J Neurosci . 2012 ; 32 : 229 - 42 .
160. Deng J , Yang M , Chen Y , Chen X , Liu J , Sun S , et al. FUS Interacts with HSP60 to Promote Mitochondrial Damage . PLoS Genet . 2015 ; 11 : e1005357 .
161. Wang W , Wang L , Lu J , Siedlak SL , Fujioka H , Liang J , et al. The inhibition of TDP-43 mitochondrial localization blocks its neuronal toxicity . Nat Med . 2016 ; 22 : 869 - 78 .
162. Wong YC , Holzbaur EL . Temporal dynamics of PARK2/parkin and OPTN/ optineurin recruitment during the mitophagy of damaged mitochondria . Autophagy . 2015 ; 11 : 422 - 4 .
163. Lopez-Gonzalez R , Lu Y , Gendron TF , Karydas A , Tran H , Yang D , et al. Poly(GR) in C9ORF72-Related ALS/FTD Compromises Mitochondrial Function and Increases Oxidative Stress and DNA Damage in iPSC-Derived Motor Neurons . Neuron. 2016 ; 92 : 383 - 91 .
164. Prause J , Goswami A , Katona I , Roos A , Schnizler M , Bushuven E , et al. Altered localization, abnormal modification and loss of function of Sigma receptor-1 in amyotrophic lateral sclerosis . Hum Mol Genet . 2013 ; 22 : 1581 - 600 .
165. Bernard-Marissal N , Medard JJ , Azzedine H , Chrast R. Dysfunction in endoplasmic reticulum-mitochondria crosstalk underlies SIGMAR1 loss of function mediated motor neuron degeneration . Brain . 2015 ; 138 : 875 - 90 .
166. Watanabe S , Ilieva H , Tamada H , Nomura H , Komine O , Endo F , et al. Mitochondria-associated membrane collapse is a common pathomechanism in SIGMAR1- and SOD1-linked ALS . EMBO Mol Med . 2016 ; 8 : 1421 - 37 .
167. Neumann M , Sampathu DM , Kwong LK , Truax AC , Micsenyi MC , Chou TT , et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis . Science . 2006 ; 314 : 130 - 3 .
168. Stoica R , De Vos KJ , Paillusson S , Mueller S , Sancho RM , Lau KF , et al. ERmitochondria associations are regulated by the VAPB-PTPIP51 interaction and are disrupted by ALS/FTD-associated TDP-43 . Nat Commun . 2014 ; 5 : 3996 .
169. Luty AA , Kwok JB , Dobson-Stone C , Loy CT , Coupland KG , Karlstrom H , et al. Sigma nonopioid intracellular receptor 1 mutations cause frontotemporal lobar degeneration-motor neuron disease . Ann Neurol . 2010 ; 68 : 639 - 49 .
170. Al-Saif A , Al-Mohanna F , Bohlega S. A mutation in sigma-1 receptor causes juvenile amyotrophic lateral sclerosis . Ann Neurol . 2011 ; 70 : 913 - 9 .
171. Fukunaga K , Shinoda Y , Tagashira H . The role of SIGMAR1 gene mutation and mitochondrial dysfunction in amyotrophic lateral sclerosis . J Pharmacol Sci . 2015 ; 127 : 36 - 41 .
172. Su TP , London ED , Jaffe JH . Steroid binding at sigma receptors suggests a link between endocrine, nervous, and immune systems . Science . 1988 ; 240 : 219 - 21 .
173. Maurice T , Junien JL , Privat A . Dehydroepiandrosterone sulfate attenuates dizocilpine-induced learning impairment in mice via sigma 1-receptors . Behav Brain Res . 1997 ; 83 : 159 - 64 .
174. Fontanilla D , Johannessen M , Hajipour AR , Cozzi NV , Jackson MB , Ruoho AE . The hallucinogen N,N-dimethyltryptamine (DMT) is an endogenous sigma-1 receptor regulator . Science . 2009 ; 323 : 934 - 7 .
175. Ruoho AE , Chu UB , Ramachandran S , Fontanilla D , Mavlyutov T , Hajipour AR . The ligand binding region of the sigma-1 receptor: studies utilizing photoaffinity probes, sphingosine and N-alkylamines . Curr Pharm Des . 2012 ; 18 : 920 - 9 .
176. Ramachandran S , Chu UB , Mavlyutov TA , Pal A , Pyne S , Ruoho AE . The sigma1 receptor interacts with N-alkyl amines and endogenous sphingolipids . Eur J Pharmacol . 2009 ; 609 : 19 - 26 .
177. Hayashi T. Sigma-1 receptor: the novel intracellular target of neuropsychotherapeutic drugs . J Pharmacol Sci . 2015 ; 127 : 2 - 5 .
178. Irwin RW , Yao J , Hamilton RT , Cadenas E , Brinton RD , Nilsen J . Progesterone and estrogen regulate oxidative metabolism in brain mitochondria . Endocrinology . 2008 ; 149 : 3167 - 75 .
179. De Nicola AF , Gonzalez Deniselle MC , Garay L , Meyer M , GargiuloMonachelli G , Guennoun R , et al. Progesterone protective effects in neurodegeneration and neuroinflammation . J Neuroendocrinol . 2013 ; 25 : 1095 - 103 .
180. Gonzalez Deniselle MC , Lopez Costa JJ , Gonzalez SL , Labombarda F , Garay L , Guennoun R , et al. Basis of progesterone protection in spinal cord neurodegeneration . J Steroid Biochem Mol Biol . 2002 ; 83 : 199 - 209 .
181. Carroll JC , Rosario ER , Chang L , Stanczyk FZ , Oddo S , LaFerla FM , et al. Progesterone and estrogen regulate Alzheimer-like neuropathology in female 3xTg-AD mice . J Neurosci . 2007 ; 27 : 13357 - 65 .
182. Kauffman FC , Sharp S , Allan BB , Burchell A , Coughtrie MW . Microsomal steroid sulfatase: interactions with cytosolic steroid sulfotransferases . Chem Biol Interact . 1998 ; 109 : 169 - 82 .
183. Su TP , Hayashi T , Maurice T , Buch S , Ruoho AE . The sigma-1 receptor chaperone as an inter-organelle signaling modulator . Trends Pharmacol Sci . 2010 ; 31 : 557 - 66 .
184. Szabo A , Kovacs A , Riba J , Djurovic S , Rajnavolgyi E , Frecska E. The Endogenous Hallucinogen and Trace Amine N,N-Dimethyltryptamine (DMT) Displays Potent Protective Effects against Hypoxia via Sigma-1 Receptor Activation in Human Primary iPSC-Derived Cortical Neurons and MicrogliaLike Immune Cells . Front Neurosci . 2016 ; 10 : 423 .
185. Su TP , Hayashi T , Vaupel DB . When the endogenous hallucinogenic trace amine N,N-dimethyltryptamine meets the sigma-1 receptor . Sci Signal. 2009 ; 2 : pe12 .
186. Mavlyutov TA , Epstein ML , Liu P , Verbny YI , Ziskind-Conhaim L , Ruoho AE . Development of the sigma-1 receptor in C-terminals of motoneurons and colocalization with the N,N'-dimethyltryptamine forming enzyme, indole-Nmethyl transferase . Neuroscience . 2012 ; 206 : 60 - 8 .
187. Szabo A , Kovacs A , Frecska E , Rajnavolgyi E. Psychedelic N , Ndimethyltryptamine and 5-methoxy- N , N-dimethyltryptamine modulate innate and adaptive inflammatory responses through the sigma-1 receptor of human monocyte-derived dendritic cells . PLoS One . 2014 ; 9 : e106533 .
188. Siskind LJ . Mitochondrial ceramide and the induction of apoptosis . J Bioenerg Biomembr . 2005 ; 37 : 143 - 53 .
189. Jana A , Hogan EL , Pahan K. Ceramide and neurodegeneration: susceptibility of neurons and oligodendrocytes to cell damage and death . J Neurol Sci . 2009 ; 278 : 5 - 15 .
190. Mavlyutov TA , Yang H , Epstein ML , Ruoho AE , Yang J , Guo LW . APEX2- enhanced electron microscopy distinguishes sigma-1 receptor localization in the nucleoplasmic reticulum . Oncotarget . 2017 ; 8 : 51317 - 51330 .
191. Schmidt HR , Zheng S , Gurpinar E , Koehl A , Manglik A , Kruse AC . Crystal structure of the human sigma1 receptor . Nature . 2016 ; 532 : 527 - 30 .
192. Ruan L , Zhou C , Jin E , Kucharavy A , Zhang Y , Wen Z , et al. Cytosolic proteostasis through importing of misfolded proteins into mitochondria . Nature . 2017 ; 543 : 443 - 6 .