Abstract
Endoplasmic Reticulum (ER) is the largest and one of the most complex cellular structures, indicating its widespread importance and variety of functions, including synthesis of membrane and secreted proteins, protein folding, calcium storage, and membrane lipid biogenesis. Moreover, the ER is implicated in cholesterol, plasmalogen, phospholipid, and sphingomyelin biosynthesis. Furthermore, the ER is in contact with most cellular organelles, such as mitochondria, peroxisomes, Golgi apparatus, lipid droplets, plasma membrane, etc. Peroxisomes are synthesized from a specific ER section, and they are related to very-long-chain fatty acid metabolism. Similarly, lipid droplets are vital structures in lipid homeostasis that are formed from the ER membrane. Additionally, there is a specific region between the ER-mitochondria interface called Mitochondria-Associated Membranes (MAMs). This small cytosolic gap plays a key role in several crucial mechanisms from autophagosome synthesis to phospholipid transfer. Due to the importance of the ER in a variety of biological processes, alterations in its functionality have relevant implications for multiple diseases. Nowadays, a plethora of pathologies like non-alcoholic steatohepatitis (NASH), cancer, and neurological alterations have been associated with ER malfunctions.
Keywords
- endoplasmic reticulum
- mitochondria
- peroxisomes
- mitochondria
- lipid droplets
- MAM
- phospholipid
- lipid metabolism
1. Introduction
The endoplasmic reticulum (ER) is a dynamic organelle largely responsible for essential cellular functions. Its wide and diverse functionality transforms the ER into a key organelle in cellular stress, signaling, vesicle transport, and lipid homeostasis. The ER is often in a state of constant change, shifting its structure to promote cell adaptation to environmental changes. For this reason, ER mass or area can fluctuate depending on cellular state and conditions.
The ER membrane is a lipid bilayer comprising two compartments: a cytosolic region in contact with the cytoplasm and a luminal region, which is the space between the two ER membranes.
In addition, two very well differentiated structures can be found within the ER: the rough endoplasmic reticulum (RER) and the smooth endoplasmic reticulum (SER). These structures have a unique architecture that is specialized for different cellular mechanisms. Specifically, RER is formed of flattened sheets and contains a large quantity of ribosomes, whereas SER has a more irregular construct, consisting of a tubular structure, and is lacking in ribosomes [1, 2, 3]. This indicates that RER is more associated with protein synthesis than SER and newly synthesized proteins in RER ribosomes could enter the RER lumen to achieve their final conformation. Therefore, in cell types that hold a high rate of protein synthesis, such as hepatocytes, it is essential that the RER is further developed [1, 4].
In contrast, SER has additional functions related to calcium storage, detoxification, lipid metabolism, steroidal hormones, and bile acid production. As a result, SER is more developed in cells with a high detoxification power, such as hepatocytes, or in both smooth and skeletal muscle cells (where SER is called sarcoplasmic reticulum). Further, since SER participates in lipid metabolism, its presence is required in adipocytes as well [1, 2, 5].
Additionally, there is a specific region within SER and RER called nanodomains, where molecules and proteins are grouped, harmonically working together to perform a precise function. Thus, proteins are not evenly distributed along with the ER but associated in clusters [6].
As mentioned, RER is specialized to accommodate both membrane and secreted protein synthesis, as well as post-translational modifications. In particular, this ER region is in contact with the nuclear envelope and allows the mRNA to enter from the nucleus to the RER lumen. The RER’s involvement in post-translational modifications includes glycosylation (N-glycosylation), sulfurization, and correct protein folding. First, RER-directed proteins must be recruited via a specific signal peptide which is recognized by the ribonucleoprotein complex SRP (Signal Recognition Particle). Once this target signal is recognized, the protein synthesis is temporarily stopped, and the ribosome, mRNA, and the newly synthesized protein are transported to the RER membrane. Here, the complex interacts with a membrane receptor and the protein is translocated to the RER lumen. Nonetheless, the mRNA continues to be translated and, at this point, protein synthesis recommences. Finally, the process ends when the entirety of the protein is in the RER lumen, and its signal peptide is cleaved by a peptidase. In the lumen, some chaperones are present in order to avoid an incorrect folding of the newly synthesized protein. There are also a plethora of enzymes that modify proteins in this region, preparing them to be secreted, for instance [4, 7, 8, 9, 10].
The ER has a “quality-control activity” that detects misfolded proteins. If the proteins cannot be successfully repaired, they are discarded and degraded. Specifically, misfolded proteins are detected by glucosyltransferase, which binds glucose to them. The bound glucose is recognized by calnexin, which attempts to correctly fold the protein on several occasions. When the problem is not solved, the misfolded protein is degraded through the proteasome, yielding amino acids that the cell can recycle into new proteins. However, when misfolded proteins reach relevant levels, they are detected by some sensors within the ER membrane. These sensors regulate cellular responses to ER stress in a process called UPR or unfolded protein response, and can imply both survival and non-survival pathways [11, 12, 13].
Despite the variety of functions of the ER, this chapter will primarily focus on two aspects: the ER’s implication in lipid metabolism, transport, synthesis, and homeostasis, and the mechanism by which the endoplasmic reticulum interacts with other organelles to achieve this.
As stated above, the ER has specific regions of contact, termed membrane contact sites (MCS), with a multitude of cellular organelles. However, it should be noted that these interactions do not imply membrane fusion but classically they have been shown to be related to calcium flux regulation (Figure 1).
Nevertheless, at present, MCS is also seen to be associated with lipid exchange, lipid synthesis (phospholipids, sphingomyelin, cholesterol, or plasmalogen biosynthesis, for example), and vesicle traffic [3, 14, 15, 16].
2. Endoplasmic reticulum and mitochondria
Mitochondria are known to be the powerhouse of the cell due to their energy production and homeostasis-related functions. For instance, some of the main processes in ATP obtention, such as the respiratory chain reactions or the Krebs cycle, occur in the mitochondria. Hence, mitochondria are especially essential in organs, tissues, or cell structures that require profuse amounts of energy, including the heart, neurons, or sperm flagella.
Interestingly, mitochondria can also enhance programmed cell death, apoptosis. Particularly, it intervenes in the intrinsic or cellular pathway, which can be activated by different cellular stimuli, including DNA damage, or ER stress. The process begins with the liberation of pro-apoptotic substances such as Cytochrome C, which participates in the respiratory chain. Cytochrome C then goes on to activate a signal cascade leading to cellular death. Clearly, mitochondria have an important involvement in some vital cellular functions, meaning its dysfunction is implicated in a large number of diseases, such as cancer, metabolic, neuronal, cardiovascular, or genetic disorders [17, 18].
Furthermore, mitochondria have unique features such as the presence of their own circular DNA as well as an inner and outer membrane. Additionally, they are highly dynamic organelles, being in a constant fusion and fission cycle based on cellular state and environmental stimuli.
Mitochondrial DNA (mtDNA) is constituted of two strands, heavy and light. The heavy strand is enriched in guanines, and codes for 12 subunits of the respiratory chain, 14 tRNAs, and two rRNAs. However, the light strand only codes for 8 tRNAs and one subunit. Despite that mitochondrial DNA does not code for a great quantity of RNAs or proteins, it is essential for good cell functionality [19, 20, 21].
Another important role attributed to mitochondria is phospholipid biogenesis, which takes place in a highly specialized association between the ER and the mitochondria called Mitochondria-Associated Membranes (MAM). Despite the fact there is currently no specified definition of exactly what MAMs are, it has been established that this area regulates processes such as apoptosis, lipid synthesis, transport, calcium homeostasis, autophagy, and mitophagy. MAMs structure is also required for phospholipids transport between the ER and the outer mitochondrial membrane (OMM) [15, 22, 23, 24].
Calcium is an essential regulatory element in mitochondria that regulates metabolism, apoptosis, and autophagy. In MAMs, calcium ion transfer to organelles is promoted due to its abundance of calcium transport channels. Specifically, mitochondria uptakes calcium ions through outer membrane voltage-dependent anion channels (VDAC) [25].
2.1 Phospholipid synthesis: ER and mitochondria cooperation
As previously explained, the endoplasmic reticulum and mitochondria coordinate together to synthesize some of the most important glycerophospholipids, such as phosphatidylcholine (PC), phosphatidylethanolamine (PE), and phosphatidylserine (PS), which represents approximately 50% of total phospholipids located in cellular membranes [26].
Glycerophospholipids are the major component in cellular membranes, both intracellular (ER, mitochondrial, and peroxisomal membranes) and extracellular facing (plasma membrane). These lipids present a polar head (phosphate group) and a hydrophobic tail, formed by fatty acids. This duality gives them an amphipathic character, endowing their characteristics to the membranes. Moreover, the hydrophobic tail can be bound with choline, ethanolamine, and serine forming, PC, PE, and PS, respectively [27, 28].
In mammals, all glycerophospholipids are synthesized from a common molecule, diacylglycerol (DAG), which derives from phosphatidic acid. Throughout the synthesis process, a large number of enzymes and many intermediate molecules are generated. The vast majority of these molecules are in the ER or the mitochondrial membrane. The first step in glycerophospholipid synthesis is phosphatidic acid generation. Two acyltransferases (glycerol-3-phosphate acyltransferase-1, GPAT1, and acylglycerophosphate acyltransferase) located in the ER and outer mitochondrial membrane must act on a glycerol-3-P molecule. The phosphatidic acid-phosphatase 1 (PAP-1), a cytosolic enzyme activated upon contact with ER membrane, acts on phosphatidic acid-generating DAG. Finally, PC, PS, and PE are synthesized from DAG [29, 30].
Mammalian cells can synthesize phosphatidylethanolamine from phosphatidylserine. In order for this to occur, PS needs to be decarboxylated by the action of an inner mitochondrial membrane enzyme, PISD (mitochondrial phosphatidylserine decarboxylase). For PE formation, an alternative synthesis pathway is utilized, the Kennedy pathway. In this pathway, ethanolamine kinase phosphorylates ethanolamine, that comes from the extracellular environment via plasma membrane, and there is several intermediate enzymatic steps, leading to the formation of PE in the ER [31].
The Kennedy pathway is also used to obtain phosphatidylcholine. When choline is in the cytoplasm, it is phosphorylated by the choline kinase. Once phosphorylated, the choline-phosphate cyticylyltransferase catalyzes CDP-choline (cytidine-5-diphosphocholine) formation. Afterward, 1,2-diacylglycerol choline phosphotransferase, transfers a DAG molecule to CDP-choline, finally generating phosphatidylcholine in the ER [32].
In parallel, PE can also be converted to PC, but PE must first be methylated three times by phosphatidylethanolamine N-methyltransferase (PEMT), which is located in ER membrane. In general, this is not a representative pathway, except for in hepatocytes, where there are significant quantities of phosphatidylcholine produced [32, 33].
There are two enzymes found in MAMs that can synthesize phosphatidylserine: PSS1 (Phosphatidylserine Synthase 1) and PSS2 (Phosphatidylserine Synthase 2). PSS1 catalyzes the exchange of choline from phosphatidylcholine for serine, whereas PSS2 performs the equivalent exchange with ethanolamine from phosphatidylethanolamine. In both cases, phosphatidylserine is obtained [34, 35].
Recently, it has been described that Mitofusin 2 (Mfn2) participates in the phosphatidylserine transport between ER and mitochondrial outer membrane. Mfn2 is a GTPase protein located in the outer mitochondrial membrane, that classically, was associated with the process of mitochondrial fusion, regulating the fusion of two OMM [36].
Beyond controlling the mitochondrial fusion process,
A probable explanation for the protective role of Mfn2 is presented in the same study; the authors demonstrated that Mfn2 has the ability to bind and help in the transfer of phosphatidylserine across ER-mitochondria contacts, generating PS-enriched domains. This facilitates PS transfer to mitochondria and further mitochondrial phosphatidylethanolamine synthesis. This transfer occurs in MAMs (Figure 2). Hence, a reduction of Mfn2 hepatic levels leads to poor PS transfer and phospholipid synthesis, causing ER stress, NASH-like phenotype, and liver cancer [15].
Additionally, Mfn2 deficiency alters PSS1 and PSS2 protein levels, inhibiting PS synthesis. This was also observed in the Mfn2 liver knock-out mouse model. The lack (or reduction) of Mfn2 also generates MAMs remodeling (altering the phospholipid composition in ER-mitochondrial contact sites). This modification leads to triglyceride accumulation, insulin resistance, and impaired phospholipid synthesis [15]. Other proteins associated with PS transport are oxysterol binding related proteins 5 and 8 (ORP 5/8) and synaptic vesicle membrane protein (VAT1) [24, 37]. ORP8 downregulation was also related to liver cancer [38]. However, whether PS deficiency is the cause, or the consequence needs to be further investigated.
3. Endoplasmic reticulum and peroxisomes
Peroxisomes are a highly versatile single membrane organelle present in many eukaryotic cells, including yeast. They can modify their morphology, size (0.2–1.5 μm), number, and activity depending on their nutritional state, cell type, or cellular environment. In mammals, peroxisomes contain a diverse range of enzymes making them organelles essential for several biochemical pathways. Some of the many roles of the peroxisome include fatty acid β-oxidation, bile acid synthesis, amino acid catabolism, polyamine oxidation, metabolism of reactive oxygen, and nitrogen species. Though all these functions are relevant, fatty acid β-oxidation is the most relevant. This process is critical for very-long-chain fatty acids (VLCFA) shortening, which mitochondria are not able to metabolize [39, 40, 41].
There are large amounts of oxidative enzymes contained within peroxisomes which can be observed in electron microscopy as crystals inside the organelle. Some of these enzymes include oxidase and catalase which use molecular oxygen to oxidize fatty and amino acids. Due to the high grade of toxicity within the peroxisome, catalase uses hydrogen peroxide (H2O2) to eliminate toxic/harmful substances, such as ethanol or methanol, or to oxidize new substrates. For this reason, peroxisomes are more abundant in cells undergoing detoxification processes, such as hepatocytes or kidney cells [39, 40, 41, 42].
It has been described that peroxisomes interact with different organelles (lipid droplets, ER, mitochondria, lysosomes, etc.) through their contact sites to maintain lipid homeostasis and metabolism. For instance, peroxisomes transform VLCFA into medium-chain fatty acids, lipids that will be converted into water and CO2 by mitochondrial action. Alterations in peroxisomes are associated with several pathologies and rare genetic diseases, usually affecting the brain, kidney, liver, and skeletal muscle. In the brain, peroxisomes play a crucial role in the synthesis of plasmalogens, a phospholipid especially enriched in myelin. Any alteration in peroxisomes will lead to severe demyelination in neurons, causing the neurological component observed in peroxisomal diseases. One example is the Zellweger syndrome, produced by a deficiency in peroxisomal biogenesis [39, 40, 42, 43, 44].
3.1 Peroxisome biogenesis: ER role
The peroxisomal membrane has a similar composition to the endoplasmic reticulum membrane. This provides a good understanding of the origin of peroxisomes; pre-peroxisomal vesicles in the ER (a specialized and delimited area of the ER). However, peroxisomes can also derive from another peroxisome through a process of fission [45]. During peroxisomal budding, a number of peroxisomal membrane proteins (PMP) are first directed to the ER, specifically in the specialized ER subdomain, from which pre-peroxisomes are budded. Pex3 and Pex19 are proteins that are particularly relevant in this process; Pex3 is a PMP located in ER membrane, while Pex19 is found in the cytosol. Pre-peroxisomal budding occurs due to an interaction between these two proteins [45, 46]. As the ER participates in peroxisomal synthesis and peroxisomes play a relevant role in lipid metabolism (plasmalogen and cholesterol synthesis), it could be suggested that the ER has an indirect function in all these processes.
3.2 Peroxisome-ER coordination in lipid homeostasis: cholesterol and plasmalogens biosynthesis
ER and peroxisomes work in coordination to maintain lipid homeostasis. There is an intimate relationship between these two organelles, transferring components and essential molecules to each other. For example, the ER transfers some important lipids to peroxisomes, whilst the ER receives some plasmalogens precursors from the peroxisome. Plasmalogens are ether phospholipids that represent approximately 20% of total phospholipids in humans. Synthesis of these molecules begins in peroxisomes and ends in the ER. As well as plasmalogens, peroxisomes can also synthesize cholesterol and part of its precursors. These precursors will then be transferred to the ER to complete their synthesis, demonstrating the complementary relationship between the ER and peroxisomes in their ability to synthesize cholesterol [39, 47, 48].
A major site of plasmalogens is in the nervous and immune system and heart; their main function is to protect these systems from oxidative damage produced by reactive oxygen species (ROS) or reactive nitrogen species (RNS). Synthesis of these molecules begins with the peroxisome phase, which initially involves esterification of dihydroxyacetone phosphate (DHAP) with an Acyl-CoA, catalyzed by DHAP acyltransferase (DHAP-AT). The resulting molecule, 1-acyl-DHAP, is then transformed to 1-O-alkyl-DHAP as a result of the action of alkyl dihydroxyacetone phosphate synthase (ADHAP-S), incorporating fatty alcohol and generating a fatty acid. Once 1-O-alkyl-DHAP is synthesized, it is transported to ER, where it will be transformed several times to obtain choline or ethanolamine plasmalogens (Figure 3). Hence, plasmalogen synthesis is another clear example of the relationship between peroxisomes and ER [39, 49, 50].
Nevertheless, the synthesis of this type of phospholipid is not the only process in which peroxisomes and the ER work together; a similar mechanism occurs with cholesterol. Principally, peroxisomes partake in the synthesis of farnesyl-pyrophosphate (FPP), an intermediate of terpenoid, terpene, and sterol biosynthesis; subsequently, the FPP generated is again transferred to the ER. Here, FPP experiences sequential modifications and finally results in the formation of cholesterol. Lastly, another means by which cholesterol synthesis can be initiated via peroxisomes is through Acetyl-CoA, derived from peroxisomal β-oxidation of very-long-chain fatty acids. Alternatively, it can continue synthesis from an intermediate, mevalonate, transferred from ER (Figure 3). In both cases, once FPP is obtained, cholesterol synthesis continues in the ER [47, 51, 52].
4. Endoplasmic reticulum and Golgi apparatus
Golgi apparatus is an organelle with two main functions: post-translational protein modification and sorting, packing, routing, and recycling membrane proteins. In the Golgi complex, four regions can be distinguished: ER-Golgi intermediate complex, cis and trans-Golgi network (the nearest and farthest cisternae to ER, respectively), and Golgi stack, which is divided into medial and trans compartments (corresponding to the central region of Golgi apparatus). Additionally, the Golgi complex has unique, biochemically distinct enzymes, that are distributed throughout its space [53, 54].
The newly synthesized proteins enter into the ER, where they are introduced into vesicles (they move from the ER-Golgi intermediate compartment to the cis-Golgi network). Finally, the vesicles reach the trans-Golgi network, which delivers these molecules to their target destinations. Despite the Golgi complex playing a fundamental role in protein transport and post-translational modifications, it is also involved in the synthesis of certain lipids, such as sphingolipids, and especially sphingomyelin, which is vital for correct cell functionality [53, 54, 55].
4.1 Golgi apparatus-ER phospholipid transport: sphingomyelin synthesis
Sphingomyelin is mainly located in the outer monolayer of the plasma membrane and is crucial for the functioning of a number of cellular processes, such as immune recognition, cell differentiation, growth, and apoptosis. Furthermore, sphingomyelin is known to be a major component of the myelin covering certain neuron axons. Namely, it binds hydrocarbon chains, improving myelin strength [56].
It is synthesized largely from ceramide and phosphatidylcholine, which are lipids obtained in the ER. Sphingomyelin synthase-1 (SGMS1), the enzyme required to synthesize sphingomyelin, is localized in the Golgi apparatus, thus its precursors must be transported from the ER to the Golgi complex.
Sphingomyelin can be obtained both in the plasma membrane and in the Golgi apparatus. Nonetheless, sphingomyelin synthesis is residual in the plasma membrane and this reaction is catalyzed by a different enzyme, sphingomyelin synthase-2 (SGMS2) [30, 57, 58].
As mentioned before, ceramide and phosphatidylcholine must be transferred from ER to the Trans Golgi network (TGN) to synthesize sphingomyelin, a process that occurs in the MCS. Ceramides are primarily located in ER membrane due to their low hydrophilicity. Moreover, this lipid can be transported to Golgi apparatus through one of two mechanisms: coatomer-dependent vesicular transport or action of a cytosolic peptide, the ceramide transfer protein (CERT). CERT transport is regulated by phosphatidylinositol-4-phosphate (PtdIns(4)P) quantity in the TGN. Once sphingomyelin is synthesized, it is transported to the plasma membrane via vesicular transport [30, 57, 58].
5. Endoplasmic reticulum and lipid droplets
Lipid droplets (LD), also known as adiposomes, are a spherical cytosolic organelle that stores triglycerides and cholesterol esters, providing an energy reserve. They are found in animals, plants, fungi, and in some bacteria. They comprise two different structures: a hydrophobic core formed by neutral lipids, and a polar phospholipid monolayer containing proteins (such as perilipin, PLIN), which partially regulate their functions. This ER-derived organelle plays a considerable role in lipid and energy homeostasis. For example, lipid droplets can generate contacts with a multitude of organelles, including mitochondria, peroxisomes, lysosomes, and the ER, allowing the transfer of lipids between them [59, 60, 61].
LD also seem to have a relevant role in infections where in some viral, fungal, or bacterial infections, microorganisms use LD in their cycle of infection. Examples that illustrate this can be seen in the case of some viruses, which exploit lipid droplets to assemble inside the cell or, on the other hand, mycobacteria and other intracellular pathogens, which steal the lipids contained in these structures to adapt themselves to the cellular environment [62]. As well as this, LD can also regulate cellular toxicity, accumulate toxic lipids, and protect vital structures from oxidative stress. Therefore, alterations in their function or physiology trigger diseases, such as NASH, obesity, or diabetes [59, 63, 64].
Depending on the cellular type, lipid droplets present distinct functionality. For instance, in adipocytes these droplets store triglycerides, waiting to be hydrolyzed when peripheral tissues require more energy. In testis, ovaries, or suprarenal glands, the lipid droplets are smaller than adipose tissue and they accumulate cholesterol esters, necessary for steroid and sex hormone synthesis. Finally, in the liver, adiposomes facilitate lipoprotein synthesis (low-density lipoprotein, LDL, and high-density lipoprotein, HDL). In mammals, tissues such as the liver, adipose tissue, and muscle contain an abundance of lipid droplets.
In addition, lipid droplet quantity is tightly associated with the nutritional status, metabolism, and nutrient availability of individuals. When there is an excess of nutrients, they are stored in lipids, increasing the number and size of lipid droplets. However, during starvation or nutrient depletion, lipids are mobilized, to synthesize the essential phospholipids or produce the required energy. Thus, lipid droplets are smaller and less abundant during this situation, especially in white adipose tissue and the liver [59, 60, 64, 65].
5.1 Lipid droplets biogenesis: ER role
As already explained, lipid droplets derive from a specific area of the ER membrane. Not only does the ER regulate and allow their genesis, but also has an important implication on lipid storage and metabolism (Figure 4).
Lipid droplets mainly store triglycerides and sterol esters, which are synthesized by enzymes mostly located in ER membrane. Prior to its incorporation into the lipid droplet, fatty acids are esterified with a sterol (to obtain a sterol ester) or diacylglycerol (to obtain a triglyceride). These reactions are catalyzed by acyl-CoA: cholesterol O-acyltransferases (ACAT1 and ACAT2), and diacylglycerol acyltransferases (DGAT1 and DGAT2), respectively. When the quantity of these lipids is significantly high, they tend to be grouped, forming what is called a “lipid lens” in the ER bilayer. It is thought that there are no proteins related to the formation of this lipid droplet precursor, due to a purely physical effect driven by their hydrophobicity characteristic. As more neutral lipids are synthesized, the lipid lenses tend to expand, eventually causing the lipid droplet to bud from ER membrane [66, 67, 68, 69].
Unlike in secretory vesicles, lipid droplet biogenesis does not appear to require coat proteins, whereas the phospholipid composition of the ER membrane would be crucial. In particular, phospholipids can influence the membrane surface tension, which is extremely important to the rounded shape purchase of LD. During this process, the neutral lipid area in contact with the aqueous media is reduced maximally and is determined by the phospholipid type dominance. For instance, while phospholipids, such as PE hinder biogenesis, lysophospholipids enhance it. These aspects also determine the gemmating direction, releasing lipid droplets into the cytosol, although they can be eventually released into the ER lumen [70, 71, 72].
Nonetheless, it has been shown that some ER membrane located proteins (storage-inducing transmembrane, FIT) regulate lipid droplet budding. More specifically, FIT proteins maintain the ER lipidic composition and shape. In the absence of FIT, the quantity of sterol esters and triglycerides in the ER membrane increases through inhibition of lipid droplet gemmation. FIT seems to act by interacting directly with DAG; hence, a lack of FIT provokes DAG accumulation in ER, which inhibits the LD budding by altering ER morphology and membrane surface tension [73, 74].
In addition, the protein Seipin is also involved in the regulation of the formation of lipid droplets. This protein has important implications in stabilizing the contact sites between the ER and LD. Furthermore, when Seipin is absent, LD formation is delayed, meaning less incorporation of lipids and proteins, and so this leads to LDs generated becoming morphologically aberrant. Moreover, a protein related to peroxisomal biogenesis, Pex30, has been described to interact with Seipin in yeast. While in normal conditions Pex30 is located along the ER membrane, in Seipin mutants, it accumulates in LD biogenesis sites. When both Seipin and Pex30 are depleted, there is no LD biogenesis, neutral lipids are accumulated in ER membrane, peroxisomes are not well synthesized, and membranes present a phospholipid disbalance, increasing PC, phosphatidylinositol, and DAG. It is observed that Pex30 works in coordination with Seipin, controlling ER membrane lipid composition, especially in LD budding areas [75, 76, 77].
Once gemmated, lipid droplets will grow through different mechanisms that include lipid transfer from ER, LD fusion, or lipid synthesis in their membrane. Triglycerides can be synthesized in LD membranes due to the transfer of specific enzymes from ER. Moreover, ER supplies all the required phospholipids for the growth to LD [78, 79].
6. Endoplasmic reticulum and plasma membrane
The plasma membrane (PM) is a phospholipid bilayer that isolates the cell content from the outside. Although PM is mainly constituted of phospholipids (such as PC, PE, and PS), it also presents cholesterol, sphingolipids, and a huge variety of proteins, which allow the signal transduction. Furthermore, PM can establish contacts with ER where phospholipid and sterol transport occur [80, 81].
6.1 Plasma membrane-ER phospholipid transport
Contacts between ER and plasma membrane are mostly related to phospholipid synthesis and its signaling. For instance, during growth factors stimulation, cells translocate PITPNM1 (membrane-associated phosphatidylinositol transfer protein 1) from the Golgi apparatus to the plasma membrane. Specifically, this lipid transfer protein transports simultaneously phosphatidic acid from PM to ER and phosphatidylinositol from ER to PM. From phosphatidic acid and phosphatidylinositol many phospholipids with regulatory functions, such as phosphatidylinositol 4-phosphate (PI4P), DAG, or phosphatidylinositol 4,5-biphosphate (PI4,5P2), can be synthesized and serve as precursors for the synthesis of PC, PS or PE. During high glucose concentration in pancreatic β-cells, it is observed another protein (phospholipid transfer protein C2CD2L, also known as TMEM24) with a similar role to PITPNM1 (it transports PI from ER to plasma membrane) [80, 82].
On the other hand, more proteins regulate lipid transport between ER and plasma membrane. For instance, ORP5/8 can transfer PS from ER to plasma membrane and PI4P in the opposite direction [80, 82]. All this continuous transport between these two organelles allows cells to main the main phospholipids levels and allows their signaling, which is essential in external and internal factors stimulation.
7. Main age-related alterations in ER and MCS
It was observed that in senescence cells, the endoplasmic reticulum increases its size, also altering its functionality. Moreover, there is variation in calcium concentration and their proteins, including chaperones, and glycosyltransferases. This alteration leads to a reduction of protein folding efficiency and an increase in misfolded protein accumulation, generating a long-term unfolded protein response. This permanent UPR activation forces cells to cell death and abnormal mitochondrial calcium signaling [83, 84, 85].
With age, alterations in MAMs, observed as an increase in the distance between ER and mitochondria, have also been seen, indicating its role in pathological conditions associated with age. This condition impairs calcium signaling and autophagy and increases ER stress. In fact, MAMs alterations have been reported in several age-related diseases, including cardiac cell senescence, cancer, inflammation, and metabolic diseases [83, 84, 85].
Apart from ER-mitochondria interactions, other types of relationships such as ER-plasma membrane, ER-Golgi, ER-lipid droplets, ER-lysosomes, ER-peroxisomes are interesting to explore in order to find out what occurs with aging.
8. Conclusions
The endoplasmic reticulum plays a central role in lipid homeostasis due to it establishing contact with essentially all cellular organelles, including mitochondria, peroxisomes, Golgi apparatus, lipid droplets, and plasma membrane (Figure 5).
To synthesize some of the more abundant glycerophospholipids, coordinated action between ER and mitochondria is needed, implicating several enzymes located in both organelles.
ER is also related to the biogenesis of peroxisomes and lipid droplets; peroxisomes interaction with ER can also generate cholesterol, essential in the plasma membrane fluidity maintenance, and plasmalogens, that protect cells from oxidative damage. As far as lipid droplets are concerned, they are generated from specific regions of the ER and their main function is to store triglycerides and cholesterol esters.
ER can also interact with the plasma membrane, exchanging phospholipids such as acid phosphatidic and phosphatidylinositol, leading to correct cellular signaling and response to extracellular stimuli. Finally, the endoplasmic reticulum also contacts the Golgi apparatus, an important event in sphingomyelin biosynthesis.
With age, it is documented that alteration in ER size and functionality, leading to a chronic UPR activation, induces apoptosis and aberrant calcium signaling. Moreover, in aging models it was an increase in ER-mitochondrial distance was also observed, also altering the ER-mitochondria communication. However, the consequences of age in the other ER contacts nowadays are unclear.
Although we have explained some of the ER interactions, there is not enough information on all the synergistic functions that the ER has. Further research is needed.
Acknowledgments
M. I. H-A acknowledges the support from the “Ayudas para contratos Ramón y Cajal (RYC) 2018” (RYC2018-024345-I) from the “Ministerio de Ciencia e Innovación” from Spain. We thank Inma Martínez-Ruiz and Alysha Jiwa for comments and the critical reading of this manuscript.
Funding
This study was supported by research grants from MICINN (PID2019-105466RA-I00 AEI/ 10.13039/501100011033 and RYC2018-024345-I MCIN/AEI/ 10.13039/501100011033) and “la Caixa” Foundation project HR21-00430.
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