Bipolar This response increases the ER protein-folding

Bipolar disorder (BD) is a chronic
psychiatric illness characterized by mood swings between maniac and depressive
states that result in cognitive and functional impairments ref 1-3 review. The pathophysiology of the
disease has been related with Endoplasmic reticulum (ER) and mitochondriaref 4 – review. ER is responsible for the
synthesis, folding and maturation of proteins, lipid synthesis and calcium
storageref5. The accumulation of unfolded
and misfolded proteins in the ER lumen originates ER stress, leading to an
activation of the Unfolded Protein Response (UPR). This response increases the
ER protein-folding capacity, reduces protein synthesis and enhance the
degradation of misfolded proteins with the aim to re-establish ER homeostasisref 7. The UPR involves three specialized
sensing proteins: PERK, IRE1? and ATF6ref 6. In resting cells,
the ER stress receptors are maintained in an inactive state through association
with the ER chaperone GRP78/BiP. ref 8. Upon
ER stress, GRP78 is released from the ER transmembrane signal transducers
leading to the activation of these UPR signalling pathways. After the
disassociation from the chaperone, PERK dissociates
from the chaperone and (acho
que a forma como escreveste dá a entender que a chaperone é GRP78)
dimerizes to promote its autophosphorylation and activation. Activated PERK
phosphorylates the eukaryotic translation-initiation factor 2a (eIF2a)
inhibiting general protein translation and preventing further protein
synthesis. However,
phosphorylated eIF2a can selectively increase the translation of mRNAs
containing inhibitory upstream open reading frames in their 5′ untranslated
region, such as activating transcription factor 4 (ATF4). This transcription
factor promotes cell survival by inducing genes involved in redox reactions,
stress response and protein secretion. However Nonetheless, one of
the downstream targets of ATF4 is a pro-apoptotic protein, CHOP. To promote
apoptosis, CHOP activates and inhibin’s inhibits (inhibin é um nome e não um verbo)
pro and anti-apoptotic proteins, respectively, and originates oxidative
stress and calcium disruption.  Therefore,
depending on the severity and duration of stress, PERK activation can lead to
either survival or cell death. ref 6,7,8
The detachment between the GRP78 and the IRE1? leads to (não sei qual a forma mais
gramaticalmente correta) an activation process similar to PERK. Its
activation (ativação do quê?
Do IRE1a, da via?) triggers a kinase activity and an endoribonuclease activity
promoting an atypical splicing of X-box-binding protein (XBP1) mRNA to form a
transcriptionally active mRNA, named XBP1s (spliced). The XBP1 translated from
the spliced mRNA is a transcription factor that regulates the expression of
genes taking part in protein folding, trafficking and ER-associated protein
degradation processes. It also inhibits CHOP expression, promoting cell
survival. During ER stress,
IRE1 (era suposto ser
IRE1a?) is switched off earlier than PERK, therefore the protective function
of IRE1 is no
longer present while PERK signalling is still enduring. Mechanisms to modulate
the duration of IRE1
signalling could therefore influence cell fate in terms of death and survival. ref 9 e 10 Dissociation of GRP78 from ATF6
allows its translocation to the Golgi where it is cleaved to its active form. Then,
(it’s vs it) translocated
to the nucleus to induce expression of genes with an ER stress response element
in their promoter. ref 11 The targets of
ATF6 include ER chaperone proteins and the transcription factor XBP1,
converging in the IRE1?
pathway. Overexpression of ATF6 can induce CHOP mRNA expression as well. When
the ER stress is chronic, a typical feature of BD, UPR fails to restore ER
homeostasis leading to autophagy and apoptosis5-8,
ref 6 a 11

Mitochondria have pivotal roles in a
variety of cellular functions, including energy metabolism, Ca2+ homeostasis,
lipid synthesis, and apoptosis. ref 12 Calcium-regulation of mitochondrial
respiration maintains ATP homeostasis. In conditions of mitochondrial Ca2+
overload, a transition pore opens (PTP), releasing cytochrome c and other
pro-apototic factors promoting cellular death by apoptosis.

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These two organelles can communicate
physically and biochemically with each other thought a contact site called
mitochondria-associated membrane (MAMs). Contact sites are specialized domains
where two membranes are closely apposed but do not fuse and thus, each
organelle maintain its identity. ref 13 – paper
mail.  MAM has a central role in the
modulation of several key processes for cell survival, such as ER stress,
autophagy, inflammasome signalling and apoptosis. ER-mitochondria juxtaposition
is determinant for cell fate under stressful conditions9-12. Sigma-1 receptor
(Sig-1R), a resident chaperone in MAMs, chaperone IRE1? to ensure the correct
transmission of ER stress into the nucleus, regulating UPR. It’s also
responsible for the attenuation of oxidative stress and cytokine signalling.
Its activation controls a variety of stress-related cellular systems.

The dysregulation of communication
between the two organelles will affect cell homeostasis, compromising the
downstream events13,14. Rise of oxidative stress is one of the consequences
of mitochondria impairment, characterized by high reactive oxygen species (ROS)
concentrations. This may be linked to inflammatory activation leading to the
assembly of the inflammasomes which are formed by microglia and
macrophages15-18 . The assembly can also result from IRE1? and PERK-mediated induction as a
result of UPR, although the mechanism isn’t
extensively described. NLRP3 inflammasome has been identified as the
characteristic active inflammasome in BD. This inflammasome is constituted by
three main components: a cytosolic receptor (NLRP3), a caspase-1 and an adaptor
protein. The assembly of this cytosolic complex maturates pro-caspase-1 into
caspase-1 leading to its activation. Caspase-1 is responsible for the
maturation of proinflammatory cytokines IL1? and IL-18, involved in neuroinflammation and
neurodegeneration that culminate in inflammatory neuronal death17,18. Since
inflammasome activation is known to have a regulatory function associated with
the specific ER-mitochondria domains, the miscommunication between organelles
and the NLRP3 activation can be correlated.

A feature of Bipolar Disorder is the
miscommunication between ER and mitochondria. As such, pharmacological
manipulation of pathways involved in the process has scientific and clinical
interest. Tunicamycin and Thapsigargin are drugs that create specific types stress
that have an impact in protein folding in the ER. Tunicamycin inhibits the
first step of glycosylation of proteins, which causes extensive protein
misfolding and activation of the UPR. ref 12
Thapsigarin inhibits ER calcium pumps, leading to an increase of cytosolic calcium.
The rise of Ca2+ disrupts the homeostasis controlled by the
mitochondria, influencing the communication between the organelles. ref 14


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