Role of ER in Maintaining Neuron Cell Homeostasis: Comparison
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Please note this is a comparison between Version 2 by Sirius Huang and Version 1 by Rafal Bartoszewski.

Efficient brain function requires as much as 20% of the total oxygen intake to support normal neuronal cell function. This level of oxygen usage, however, leads to the generation of free radicals, and thus can lead to oxidative stress and potentially to age-related cognitive decay and even neurodegenerative diseases. The regulation of this system requires a complex monitoring network to maintain proper oxygen homeostasis. Furthermore, the high content of mitochondria in the brain has elevated glucose demands, and thus requires a normal redox balance. Maintaining this is mediated by adaptive stress response pathways that permit cells to survive oxidative stress and to minimize cellular damage. These stress pathways rely on the proper function of the endoplasmic reticulum (ER) and the activation of the unfolded protein response (UPR), a cellular pathway responsible for normal ER function and cell survival.

  • endoplasmic reticulum stress
  • mitochondria unfolded protein response
  • oxidative stress
  • neurodegeneration
  • proteostasis
  • calcium
  • brain
  • nitrosative stress
  • oxygen homeostasis

1. Introduction

Proper oxygen (O2) homeostasis is essential for human survival, and the human brain consumes about 20% of the total oxygen to support neurons and glia [1,2,3,4][1][2][3][4]. Unmet brain oxygen needs during ischemic stroke limit ATP synthesis [5,6][5][6]. Oxygen consumption results in the generation of free radicals and non-radicals including superoxide (O2.-) and hydroxyl anions (.OH), and hydrogen peroxide (H2O2) [7,8,9,10][7][8][9][10]. Although this is an unavoidable consequence of oxygen-dependent brain activity, if not controlled properly, it leads to oxidative stress and neurodegeneration [11,12,13,14,15,16,17,18,19][11][12][13][14][15][16][17][18][19]. Thus, maintaining proper oxygen homeostasis in brain tissues requires a balanced level of O2-derived free radicals and non-radicals [1]. 
Given that maintaining the redox balance is necessary for cell survival, it is surprising that the brain is so susceptible to oxidative stress and oxidative damage [1]. This vulnerability to brain oxygen damage is believed to be a compromise between brain function and the biochemical organization that is required for survival [20]. This organization includes a high content of mitochondria, an increased glucose demand, and a high influx of neuronal Ca2+. Furthermore, there is increased microglia activity, as well as increased neuronal nitric oxide synthase (nNOS) and nicotinamide adenine dinucleotide phosphate (NAPDH) oxidase (NOX) signaling, along with the presence of autoxidizable neurotransmitters. This metabolism machinery generates hydrogen peroxide, high concentrations of peroxidable lipids, elevated levels of cytochrome P450, and the enrichment of brain tissues in redox-active transition metals such as Fe2+ and Cu+ [1,11,12,13,14,15,16,17,18,19,21,22][1][11][12][13][14][15][16][17][18][19][21][22]. All of this leads to potential stress that needs to be properly and safely regulated.
In this complex system, brain cells have to efficiently modulate their signaling pathways to maintain their redox balance and utilize universal adaptive stress responses in order to survive periods of elevated oxidation levels and minimize cellular damage. These stress pathways depend on the proper function of the endoplasmic reticulum (ER) and activation of the unfolded protein response (UPR), a set of complex molecular pathways that regulate proper ER function required for cell survival, or in the case of unmitigated cell stress, lead to cell death. 

2. Role of the ER in Maintaining Neuron Cell Homeostasis

2.1. Calcium Regulation and Signaling

Connecting synaptic activity with the biochemical signals of neurons occurs through utilizing calcium ions (Ca2+) as the main second messenger to regulate activity-dependent signaling [25,26][23][24]. Brain calcium fluxes lead to high ATP demands that restore the ion levels after calcium influx through the plasma membrane receptor. When impaired, intracellular calcium homeostasis leads to increased generation of mitochondrial reactive oxygen species (ROS) [27][25]. The ER, the main cellular calcium storage compartment, remains a critical system responsible for the calcium balance in neurons [28][26]. ER calcium release in response to small increases in its cytosolic levels is termed calcium-induced calcium release (CICR), whereas the reduction in calcium concentration in ER lumen is referred to as storage-operated calcium entry (SOCE) [28][26]. Both of these mechanisms amplify cytosolic calcium levels and allow the ER, at least in theory, to generate calcium transients independently of any plasma membrane depolarization [29][27]. Furthermore, ER calcium release and uptake in neurons relies on the membrane potential and contributes to its modulation by accelerating increases and decreases in the calcium cytosolic levels.
The excessive influx of calcium into neurons mainly occurs through the activation of N-methyl-D-aspartate (NMDA) receptors by glutamate, and results in CICR [28][26]. Although the influx of calcium through NMDA receptors is the underlying basis of neurodegeneration caused by excitotoxicity, calcium stores within the endoplasmic reticulum (ER) can also be released through ryanodine receptors (RyR) and inositol 1,4,5-trisphosphate receptors (IP3R) under these conditions, and this can amplify the pathological calcium signals [28,29][26][27]. As a consequence, the activation of the mitochondrial calcium buffering system can occur and lead to rapid mitochondrial damage due to increased permeability of the transition pore (mPTP) [28,30,31][26][28][29]. Furthermore, the increase in intracellular calcium concentration is accompanied by O2- release and the generation of OH. in the Fenton reaction, which is catalyzed by superoxide dismutase (SOD) [32,33][30][31].
ER calcium release in the region of mitochondria-associated membranes (MAMs) [34,35][32][33] has been shown to support the ATP demand-related mitochondrial uptake of calcium [36,37][34][35]. Mitochondrial calcium uptake leads to increases in the activity of the Krebs cycle enzymes [36,37,38,39][34][35][36][37]. Despite multiple pathways that allow mitochondrial calcium release that include both ion exchangers and the transient opening of the mitochondrial permeability transition pore (mPTP) [30[28][29],31], mitochondria remain prone to calcium overload. This unfortunately leads to reduced ATP synthesis, increased ROS formation [40[38][39],41], and eventually cell death [42][40]. This highlights the importance of the cooperation between mitochondria and ER in regulating intracellular calcium levels and neuronal cell viability.

2.2. The ER and Proteostasis

The spatial organization of the brain dependence on this complex neuronal structure is maintained by the continuous protein profile-related remodeling of synapses [43,44,45][41][42][43]. Their proper function relies on the biogenesis of plasma membranes that are enriched with specific proteins, including cell adhesion molecules, ion channels, receptors, and transporters [46][44]. The ER is a central compartment for the secretory protein pathway, which is important for membrane protein maturation and lipid biosynthesis, and this pathway remains critical both during and after brain development [47,48][45][46]. Proper ER functions are crucial for both synapse formation and plasticity as well for cognitive functions [47,48,49,50,51][45][46][47][48][49].
The ER also contains enzymes and chaperones that assist in various protein folding scenarios and mediates their posttranslational maturation [52][50]. This protein maturation machinery includes chaperone immunoglobulin binding protein (BiP; also known as HSPA5 or Grp78) [53][51], different oxidoreductases of the protein disulfide isomerase (PDI) family [54][52], and the peptidyl prolyl cis-trans isomerases (PPIs) [55][53]. Protein quality control of the ER-maturating glycosylated proteins is ensured by the calnexin–calreticulin system [56][54], whereas terminally misfolded peptides are exported from the ER and degraded either by the proteasome (ER-associated degradation (ERAD)) or the lysosome (ER-to-lysosome-associated degradation (ERLAD)) [57,58][55][56]. Random oxidation of mRNA is one of the consequences of the brain oxygen burden [59][57], and this can increase translational errors [60][58], reduce the successful protein folding in ER [61[59][60][61],62,63], and provide challenges for the ER-associated degradation system. Furthermore, impaired efficiency of ER-related protein maturation can result in deregulation of brain redox homeostasis and lead to oxidative damage. Oxidative stress can also impair ER proteostasis and ER-associated degradation, leading to accumulation and aggregation of misfolded proteins, as is observed during neurodegeneration [64,65][62][63].

2.3. The ER Lipid Biosynthesis

ER-localized enzymes are also responsible for the synthesis of the majority of cellular lipids that are another key component of the brain. These membrane lipids allow the brain cells to grow, proliferate, differentiate, and modulate neurons and glia cell function, including neurotransmission [66,67,68][64][65][66]. Interestingly, the brain is enriched in long-chain polyunsaturated fatty acids that are sensitive to oxidation, but neurons do not store energy in the form of glycogen or lipid droplets. Therefore, fatty acid oxidation primarily occurs in astrocytes that transfer the related metabolites to neurons [69][67]. Furthermore, stressed neurons release peroxidated fatty acids to be endocytosed and stored in lipid droplets by neighboring astrocytes that utilize this storage to support the stimulated neuron energy requirements [70][68]. This lipid crosstalk between the neurons and astrocytes ensures proper brain function, while minimizing the risk of oxidative stress [69][67]. This cooperation between the neurons and astrocytes prevents a buildup of peroxidated fatty acids in neurons during periods of prolonged stimulation [70][68].
Cholesterol, on the other hand, is enriched in synaptic membranes and serves as a regulator of neurotransmissions. It is synthetized de novo in both neurons and astrocytes [71,72][69][70]. The cholesterol synthesis pathway is dependent upon the ER-associated sterol regulatory element-binding protein (SREBP) system that is activated by low cholesterol levels in ER membranes and is very sensitive to the alterations in ER homeostasis [73,74][71][72].
In summary, ER homeostasis (as presented in Figure 1) remains one of the key factors for brain development and function, including the redox balance. ER homeostasis is stabilized by the presence of the UPR. The UPR promotes cellular survival by reducing ER damage during stress, or alternatively promotes cell death during prolonged or unmitigated stress [75][73]. This negative scenario is a common characteristic of neurodegenerative diseases caused by aggregates of mutant proteins or through loss of function of genes responsible for proteostasis [75,76,77,78][73][74][75][76]. Thus, the ability of UPR to determine cell fate is a crucial element of brain aging and potential neurodegeneration.
Figure 1. The role of the endoplasmic reticulum (ER) in maintaining neuron cell homeostasis. (A) As the main Ca2+ reservoir, the ER is crucial for the regulation of cytosolic Ca2+ concentration using pumps and channels localized in ER membrane. Those include sarco/endoplasmic reticulum Ca2+ ATPase (SERCA), Ca2+-activated ryanodine receptors (RyRs), and inositol-1,4,5-trisphosphate (IP3)-gated IP3 receptors (IP3Rs). They cooperate with the cell membrane Ca2+ transporters that regulate the influx of extracellular Ca2+, exemplified by plasma membrane Ca2+ ATPase (PMCA) and N-methyl-D-aspartate receptor (NMDAR). (B) Ca2+ homeostasis processes in the ER and mitochondrion are tightly interconnected, primarily by virtue of the regions of mitochondria-associated membranes (MAMs). An increase in Ca2+ concentration in MAM promotes its influx into the mitochondrion, mainly through voltage-dependent anion channel (VDAC). High Ca2+ concentration stimulates the activity of the oxidative processes in the mitochondrion, leading to the increased production of reactive oxygen species (ROS). In turn, ROS-dependent modifications of ER Ca2+ channels increase their permeability for Ca2+ and the efflux of Ca2+ from ER, which closes the positive-feedback loop. (C) The ER is a central cell compartment where the synthesis and quality control of secretory and membrane proteins takes place. The properly folded proteins are directed through secretory pathway to the cell membrane, whereas irreversibly unfolded/misfolded proteins are exported and eventually degraded either in lysosomes or proteasomes. (D) ER-based lipid crosstalk between neurons and astrocytes. Fatty acids (FAs) and the products of their oxidation synthesized in astrocytes are delivered to neurons to support their demand for energy and membrane building components. In turn, nonfunctional peroxidated FAs released by neurons are endocytosed by astrocytes and stored in lipid droplets or catabolized by the mitochondrial FA oxidation pathway.

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