How do nucleus and er work together

Structurally, the endoplasmic reticulum is a network of membranes found throughout the cell and connected to the nucleus. For example, some cells, such as prokaryotes or red blood cells, do not have an ER of any kind. Cells that synthesize and release a lot of proteins would need a large amount of ER.

You might look at a cell from the pancreas or liver for good examples of cells with large ER structures. Rough and Smooth There are two basic types of ER.

Both rough ER and smooth ER have the same types of membranes but they have different shapes. Rough endoplasmic reticulum is named for its rough appearance due to ribosomes attached to its folds. This is where most protein synthesis occurs. Ribosomes are usually attached to the rough endoplasmic reticulum but may also float freely in the cytoplasm.

They are the main site of protein synthesis. The Golgi apparatus functions like a post office. Proteins are packaged and sent to the Golgi apparatus for distribution. Vesicles are formed and then delivered to the site on the cell membrane where they release protein molecules during exocytosis or envelop external substances and incorporate them into the cell during endocytosis.

Some of the protein-carrying vesicles remain in the Golgi apparatus for storage. The Golgi complex is also responsible for making lysosomes. Vesicles are small sacs that contain substances and transport them around the cell. They also carry substances in and out of the cell. Vesicles transport substances from the site of synthesis to the cell membrane for export and from the cell wall to other organelles with imported substances.

The plasma membrane is a two-layer barrier that separates the cell from its environment and allows certain substances to be imported or exported. Calcium is released via inositol 1,4,5 trisphosphate receptor IP3R of the endoplasmic reticulum ER and provides a relatively high calcium environment for mitochondria. Calcium enters the mitochondrial matrix through the voltage-dependent anion channels VDACs on the outer mitochondrial membrane OMM and through the low-affinity receptor, mitochondrial calcium uniporter MCU on the inner mitochondrial membrane IMM.

In addition, IP3R is regulated by numerous regulatory mechanisms. After lipid synthesis in the mitochondria or ER, a large amount of lipids is exchanged between the mitochondria and the ER in order to achieve the final lipid composition of the two organelles. This includes the processes of phosphatidylethanolamine PE and phosphatidylcholine PC synthesis and cardiolipin CL synthesis. Calcium is a very important intracellular regulatory molecule. It regulates a variety of physiological and pathological processes, including cancer, and an increasing number of studies have shown that oncogenes and tumor suppressors are also related to the calcium transport system Fig.

Mitochondria and ER are important storage organelles of calcium in the cell, and calcium transfer between organelles is crucial for cell life and death [ 7 , 8 ]. Calcium enters the mitochondria from the ER through MAMs and plays an important role in mitochondrial division and control of apoptosis. The uptake of calcium in the mitochondrial matrix is mainly accomplished by the low-affinity mitochondrial calcium uniporter MCU receptor on the inner mitochondrial membrane IMM , and calcium passes through the outer mitochondrial membrane OMM relatively easily, mainly via the voltage-dependent anion channels VDACs [ 9 , 10 , 11 ].

Therefore, to promote the efficient uptake of calcium by mitochondria, it is necessary to generate locally high concentrations of calcium in MAMs. Under the action of IP3R and other signals, calcium in the ER is rapidly released into the surrounding cytoplasm through IP3R, exposing mitochondria to higher concentrations of calcium [ 12 , 13 ].

Calcium transfer can be terminated by increasing the distance of MAMs [ 13 , 14 ]. In mammalian cells, mitofusin 2 MFN2 , a family member of mitochondrial dynamics, is located in the OMM and ER surface, regulating the organelle connection between calcium-transfer sites [ 15 , 16 , 17 ]. Efficient IP3R-mediated calcium transfer to the mitochondria is achieved by the chaperone protein, a kDa glucose regulatory protein GRP However, this sensitive system can be utilized to achieve malignant transformation of cells.

Several types of cancer cells undergo extensive reorganization of calcium signaling mechanisms to become conducive to tumorigenesis [ 19 ]. Additionally, the presence of proteins encoded by oncogenes and tumor suppressors in MAMs may alter calcium signaling in cancer cells.

Recent studies showed that disturbance in calcium homeostasis is an important mechanism of oncogene-encoded proteins and tumor suppressors to affect cancer cell fate [ 20 ]. Because IP3R is an important calcium transport system that maintains calcium homeostasis between the ER and mitochondria, some oncogene-encoded proteins and tumor suppressors have been shown to modulate IP3R activity. Therefore, IP3R is considered a molecular target for the action of oncogene-encoded proteins and tumor suppressor factors in cancer cells Fig.

IP3R is regulated by a variety of mechanisms. Different signals are brought together and converted to calcium signals, further affecting the function of mitochondria and even cells [ 21 ].

IP3R is over-phosphorylated in cancer cells upregulated by AKT [ 22 ]; therefore, calcium flow from the ER to mitochondria decreases, which protects cancer cells from mitochondrion-mediated apoptosis. Thus, phosphorylated IP3R is regulated by numerous different oncogene-encoded proteins and tumor suppressors, including AKTs lipid phosphatase and negative regulators, phosphatase and tensin homolog on chromosome 10 PTEN [ 23 ], p53 proteins [ 24 ], and promyelocytic leukemia PML proteins.

This leads to phosphorylation of AKT, which phosphorylates IP3R and inhibits the release of calcium from protein IP3R, further protecting the mitochondria from calcium-mediated apoptosis [ 25 ]. PML is an effective tumor suppressor protein that stabilizes p53 protein and improves its function. Deletion of PML is associated with malignant pleural mesothelioma, breast cancer, etc.

Additionally, PML inhibits the formation of autophagosomes, thereby inhibiting autophagy induction. Decreased PML levels can also promote tumor growth by enhancing cellular autophagy [ 24 ]. Some anticancer drugs target the calcium-connected pathways [ 28 ]. For example, arsenic trioxide has a significant effect on chemotherapy for acute promyelocytic leukemia by specifically targeting PML.

Bcl-2 family proteins in the ER play an important role in apoptosis by controlling the integrity of mitochondrial membrane, the release of cytochrome C, and the activation of caspases [ 29 ]. It has been reported that Bcl-2 family proteins regulate the activity of IP3R [ 30 ], and different Bcl-2 proteins bind to IP3R at different sites and play different roles Table 1. For example, Bcl-2 binds to the central region of IP3R, thereby inhibiting the function of IP3R and reducing the release of calcium, which leads to the inhibition of the apoptotic signal.

It is regulated by several proteins at the ER-mitochondrial contact site to affect calcium flux. Regulation of the activity of the SERCA pump by proteins encoded by oncogenes in MAMs and tumor suppressor factors is also important for the development of tumor cells. When apoptosis is triggered, the ER releases a large number of calcium ions, which enter the mitochondria to cause a calcium ion overload and induce apoptosis. However, in cancer cells, TP53 may be mutated or the p53 protein is inactivated, and thus, the ER cannot maintain a state of relatively high calcium ions, enabling cancer cells to escape apoptosis Fig.

In cancer, STIM and ORAI isoforms display increased expression in numerous tumor types and are associated with signaling pathways that positively regulate cancer cell proliferation, migration, invasion, and chemoresistance [ 37 , 38 ]. The response of ER to cellular stress is linked to the accumulation of unfolded proteins and called unfolded protein response UPR.

UPR is activated in response to the accumulation of unfolded or misfolded proteins accumulated in the ER. UPR stops protein translation, degrades misfolded proteins, and activates signaling pathways to restore the normal function of cells.

As a large number of molecular chaperones assist in the folding of unfolded proteins, they consume a large amount of ATP. Therefore, in order to increase the production of ATP, cells usually increase the contact area between ER and mitochondria, which in turn increases the release of calcium from the ER, causing calcium to flow into mitochondria [ 63 ]. If UPR does not reduce cell stress, the ER and mitochondrial contact points resulting from the above process increase, calcium release increases, and mitochondria uptake calcium, leading to apoptosis Fig.

In cancer cells, UPR is constitutively activated. During tumor development and growth, abnormal cell proliferation requires higher protein synthesis, and cancer cells are subjected to various pressures such as hypoxia, low glucose, low pH, and lack of nutrition, which induce UPR [ 64 ].

Hence, only PERK is described below. Activation of PERK signaling and integrated stress response ISR is considered a necessary condition for tumor survival under conditions of hypoxia and nutrient deficiency [ 66 ]. The PERK-specific inhibitor GSK was reported to inhibit angiogenesis and amino acid metabolism, thus preventing tumorigenesis in vivo [ 62 ]. Studies showed that PERK is involved in the adaptation of cancer cells to the challenges of the tumor microenvironment [ 68 , 69 , 70 ].

Phospholipids are a major component of all cell membranes, and the ER is the main site of phospholipid synthesis in cells. Phospholipids are normally transported in vesicles to their destination after synthesis in the ER.

However, for transport into the mitochondria, phospholipids are directly imported through the membranes [ 72 , 73 ]. MAMs do not only control the lipid membrane homeostasis of mitochondria and ER but also support the transfer of different lipids and have biological effects on cell fate [ 74 ]. A large number of lipid-metabolizing enzymes are abundant in MAMs, where lipid metabolism is also performed [ 8 ] Fig. One manner in which tumor cells inhibit mitochondrial metabolism and apoptosis signals is to alter the ER lipid structure, thus destroying the normal MAM raft.

Therefore, in order to achieve the final lipid composition of both organelles, a large amount of lipid exchange must be performed between these two organelles. In addition, phosphatidic acid is an important source material for the synthesis of cardiolipin CL. It is converted into cytidine diphosphate diacylglycerol by the mitochondrial translocator assembly and maintenance protein 41 homolog Tam41 in the IMM [ 76 ].

Next, cytidine diphosphate diacylglycerol further synthesizes glycerolphosphate phosphatase with glyceraldehyde 3-phosphate under the catalysis of phosphatidylglycerophosphate synthase 1; glycerolphosphate phosphatase is dephosphorylated by the phosphatase Gep4 to generate phosphatidylglycerol [ 77 ]. Although phosphatidylglycerol is only present in small quantities in the mitochondria, it plays an important role in CL synthesis [ 78 ], catalyzed by CL synthase Crd1 [ 79 ].

Analysis of the intimal lipid composition of various tumor mitochondria revealed that its cholesterol content was high, and changes in fatty acyl components were observed.

Mitochondrial phospholipids in tumor cells are typically shorter than those in normal cells and unsaturated acyl chains are shorter [ 80 , 81 ]. The composition and content of CL is significantly altered in some tumors [ 82 ], which is likely related to defects in CL synthesis and remodeling.

In addition, MAMs contain enzymes that are necessary for cholesterol and ceramide biosynthesis [ 83 , 84 ]. In hepatocytes, acetyl-CoA acetyltransferase, mitochondrial ACAT1 in the MAM catalyzes the formation of cholesterol esters in the resting state, thereby controlling the balance between membranous and cytoplasmic lipids and low-fat cholesterol.

In response to stress, cholesteryl esters are continuously introduced into the mitochondria, and cytochrome P initiates steroidogenesis [ 83 ]. Ceramide synthetized in the ER flows into the mitochondria and permeabilizes the OMM to apoptotic-inducing proteins, thus initiating apoptosis. Considering the pro-apoptotic properties of ceramide in the mitochondria, MAM may act as an important reservoir or barrier to prevent the influx of ceramide into the mitochondria.

Cholesterol metabolism is deregulated in carcinogenesis, and cancer cells exhibit increased mitochondrial cholesterol content. Changes in mitochondrial cholesterol transport and metabolism in cancer cells affect the biophysical properties and mitochondrial functions of mitochondrial membranes. Compared to normal cells, the mitochondria of cancer cells are more susceptible to increased cholesterol, which triggers ER stress and apoptosis [ 85 ]. Ceramide is considered a tumor suppressor lipid because of its important role in regulating the physiological and drug-induced apoptosis of cells.

The production of ceramide under the action of SMase was shown to be important in the regulation of cancer progression. Inhibition of SMase is related to drug resistance to a variety of anticancer drugs [ 86 ]. CerS expression was also shown to modulate the sensitivity to cancer chemotherapy drugs and radiotherapy.

Overexpression of CerS1 in hek cells was shown to make these cells sensitive to some anticancer drugs, such as cisplatin, carboplatin, doxorubicin, and vincristine. Peroxisomes are ubiquitous and dynamic single membrane-bound organelles in cells, who modulate their numbers, morphology, and activity to adapt to diverse environments in different tissues, organs, and nutritional states [ 87 , 88 , 89 ].

Among them, mitochondria and peroxisomes interact very closely. In this series of processes, mitochondria and peroxisomes can complete various biological functions through vesicles transport, signaling molecules, and membrane contact sites [ 90 ]. They also exhibit a close interplay in generation, fission, proliferation, and degradation [ 90 ]. The integrity and stability of peroxisomes are important guarantees for the maintenance of normal mitochondrial function.

Peroxisomal dysfunction seriously affects mitochondrial metabolism, morphological stability, and biosynthesis, which directly or indirectly lead to rare genetic diseases, such as X-linked adrenoleukodystrophy, acatalasemia, and Zellweger syndrome, and relatively common age-related disorders, such as diabetes, neurodegenerative disease, and cancer [ 87 , 91 ]. Mitochondria participate in the formation of peroxisomes. In mammals, peroxisomes can be produced by asymmetric growth and division from pre-existing organelles, as well as by the fusion of pre-peroxisomes from the ER and mitochondria [ 87 , 91 ], allowing the transport of functional proteins and other compounds from the mitochondria into peroxisomes, which may be one of the reasons why peroxisomes and mitochondria have many similar functions [ 91 ] Fig.

The connection between peroxisomes and mitochondria. Mitochondria can communicate with peroxisomes via vesicular transport of MDVs. Both mitochondria and peroxisomes can produce ROS, and they are also important organelles for removing ROS and ensuring cell stability. Peroxisomes mainly contain catalase to break down H 2 O 2. ROS are also important signaling molecules, which can induce cell apoptosis. The function of mitochondrial and peroxisomal coordination cannot be separated from the transcriptional regulation mechanism, including peroxisome proliferator-activated receptors PPARs , whose different subtypes have different tissue expression patterns and substrate specificities as well as regulate different target genes [ 91 , 92 ].

PPARs form a sub-family of nuclear hormone receptors that function as ligand-activated transcription factors to regulate various biological processes [ 93 ].

The activity of PPARs is also regulated by many transcriptional coactivators and co-repressors [ 87 , 91 ]. Both peroxisomes and mitochondria can be generated by fission from pre-existing organelles and share many proteins involved in division [ 98 ].

Mitochondrial fission 1 FIS1 protein, mitochondrial fission factor MFF , and ganglioside-induced differentiation-associated protein GDAP 1, membrane adapter proteins located on the mitochondria and peroxisomes membranes recruit dynaminlike protein DNM1L to the organelle cleavage site to disrupt organelles through a series of downstream post-transcriptional modifications.

Overexpression or downregulation of membrane adaptor proteins induces splitting or elongation these two organelles, respectively [ 91 , 98 , 99 ] Fig. Dysfunctional and impaired peroxisomes in cells can be cleared by the lysosomal autophagy pathway called pexophagy [ ]. The mitochondria are cleared by mutual fusion and phagocytosis by lysosomes called mitophagy [ ]. A number of studies have shown that when the peroxisomal function is impaired, mitochondria can exert compensatory effects by increasing their volume through autophagy, but the specific molecular mechanism is not yet clear [ 91 ].

Mitochondria and peroxisomes are closely linked through membrane contact sites. In the past, researchers verified the close relationship between the two organelles by studying their spatial structure by using a series of experimental methods [ 88 , ]. In mammalian cells, mitochondria and peroxisomes contact each other through a complex whose core component is a splice variant of enoyl-CoA isomerase 2, which contains the targeting signals to mediate the close contact between the two organelles [ 91 ].

In yeast, peroxin, the most abundant peroxisomal membrane protein, is involved in peroxisome generation and composition, which regulates the division of peroxisomal membranes during proliferation [ ].

The ER-mitochondrial encounter structure ERMES complex serves as a bridge between molecular exchanges and tight links of mitochondria and ER, whereas peroxin binds to the mitochondrial component Mdm34 of the ERMES complex to mediate and promote information transfer between mitochondria and peroxisomes [ ] Fig. Mitochondria can also communicate with peroxisomes via vesicular transport of mitochondria-derived vesicles [ 98 ]. Among them, mitochondrial anchored protein ligase promotes the division of mitochondrial membrane and leads to the formation of vesicles [ 98 , 99 ].

Next, the mitochondrial vesicles with mitochondrial anchored protein ligase fuse with peroxisomes. This fusion promotes the production of peroxisomes and transports certain specific metabolites and needed proteins to the peroxisomes [ 98 , 99 ].

In addition, mitochondria and peroxisomes can be linked by the release of biological messengers, including ROS, lipids, or other metabolites, and this process is closely related to the size of the molecules and the permeability of the organelle membranes [ 87 ] Fig. Dietary fatty acids such as palmitic acid, oleic acid, and linoleic acid are preferentially metabolized in mitochondria, and most carboxylic acid esters such as very-long-chain fatty acids, pristanic acid, other 2-methyl-branched prostanoids, and bile acid intermediates are more likely to be metabolized in peroxisomes [ 87 , 91 ].

The acetyl-CoA is used to generate energy in the tricarboxylic acid cycle, and lipids in the mitochondria eventually produce CO 2 and H 2 O [ 98 , 99 ] Fig. When catalase function is altered or its production in peroxisomes is disturbed, it will lead to mitochondrial oxidative stress response and, in severe cases, IMM structure alteration, changes in respiratory chain complex activity, DNA damage, and increased organelle volume, which can further cause oxidative stress damage to the entire cell [ , ].

Studies have shown that when ROS in peroxisomes exceeds a certain level, ROS level in mitochondria increases, and the redox balance in mitochondria is disturbed, causing mitochondrial breakdown and cell death [ , , ]. In addition, ROS are important signaling molecules in cells, which can cause mitochondrial and peroxisomal autophagy and apoptosis [ ].

When ROS level increases in cells to induce oxidative stress, the expression of starvation-induced protein DEPP is upregulated, which further induces autophagy, thereby protecting cells from injury [ ].

Although how mitochondria and peroxisomes communicate through ROS has not been elucidated in detail, it is possibly through intracellular diffusion, potential contact sites, or vesicle trafficking [ ] Fig. Mitochondria and peroxisomes are important organelles in the production and clearance of ROS. Impaired peroxisomal function inevitably leads to an increase in ROS level in mitochondria, which damages the mitochondria and aggravates ROS clearance disorders, thereby promoting the occurrence and development of tumors [ ] Table 2.

Subsequently, the rest of the cell's organelles use this ATP as the source of the energy they need to operate. Because most organelles are surrounded by membranes, they are easy to visualize — with magnification. For instance, researchers can use high resolution electron microscopy to take a snapshot through a thin cross-section or slice of a cell.

In this way, they can see the structural detail and key characteristics of different organelles — such as the long, thin compartments of the endoplasmic reticulum or the compacted chromatin within the nucleus. An electron micrograph therefore provides an excellent blueprint of a cell's inner structures. Other less powerful microscopy techniques coupled with organelle-specific stains have helped researchers see organelle structure more clearly, as well as the distribution of various organelles within cells.

However, unlike the rooms in a house, a cell's organelles are not static. Rather, these structures are in constant motion, sometimes moving to a particular place within the cell, sometimes merging with other organelles, and sometimes growing larger or smaller. These dynamic changes in cellular structures can be observed with video microscopic techniques, which provide lower-resolution movies of whole organelles as these structures move within cells. Of all eukaryotic organelles, the nucleus is perhaps the most critical.

In fact, the mere presence of a nucleus is considered one of the defining features of a eukaryotic cell. This structure is so important because it is the site at which the cell's DNA is housed and the process of interpreting it begins. Recall that DNA contains the information required to build cellular proteins. In eukaryotic cells, the membrane that surrounds the nucleus — commonly called the nuclear envelope — partitions this DNA from the cell's protein synthesis machinery, which is located in the cytoplasm.

Tiny pores in the nuclear envelope, called nuclear pores, then selectively permit certain macromolecules to enter and leave the nucleus — including the RNA molecules that carry information from a cellular DNA to protein manufacturing centers in the cytoplasm.

This separation of the DNA from the protein synthesis machinery provides eukaryotic cells with more intricate regulatory control over the production of proteins and their RNA intermediates. In contrast, the DNA of prokaryotic cells is distributed loosely around the cytoplasm, along with the protein synthesis machinery.

This closeness allows prokaryotic cells to rapidly respond to environmental change by quickly altering the types and amount of proteins they manufacture. Note that eukaryotic cells likely evolved from a symbiotic relationship between two prokaryotic cells, whereby one set of prokaryotic DNA eventually became separated by a nuclear envelope and formed a nucleus.

Over time, portions of the DNA from the other prokaryote remaining in the cytoplasmic part of the cell may or may not have been incoporated into the new eukaryotic nucleus Figure 3.

Figure 3: Origin of a eukaryotic cell. A prokaryotic host cell incorporates another prokaryotic cell. Each prokaryote has its own set of DNA molecules a genome. The genome of the incorporated cell remains separate curved blue line from the host cell genome curved purple line. The incorporated cell may continue to replicate as it exists within the host cell. Over time, during errors of replication or perhaps when the incorporated cell lyses and loses its membrane separation from the host, genetic material becomes separated from the incorporated cell and merges with the host cell genome.

Eventually, the host genome becomes a mixture of both genomes, and it ultimately becomes enclosed in an endomembrane, a membrane within the cell that creates a separate compartment. This compartment eventually evolves into a nucleus. Figure Detail. Besides the nucleus, two other organelles — the mitochondrion and the chloroplast — play an especially important role in eukaryotic cells. These specialized structures are enclosed by double membranes, and they are believed to have originated back when all living things on Earth were single-celled organisms.

At that time, some larger eukaryotic cells with flexible membranes "ate" by engulfing molecules and smaller cells — and scientists believe that mitochondria and chloroplasts arose as a result of this process.