Mitochondria-associated membranes (MAM) represent a region of the endoplasmic reticulum (ER) which is reversibly tethered to mitochondria. These membranes are involved in import of certain lipids from the ER to mitochondria and in regulation of calcium homeostasis, mitochondrial function, autophagy and apoptosis. They also play a role in development of neurodegenerative diseases and glucose homeostasis. [1]
In mammalian cells, formation of these linkage sites are important for some cellular events including:
Mitochondria associated membranes are involved in the transport of calcium from the ER to mitochondria. This interaction is important for rapid uptake of calcium by mitochondria through Voltage dependent anion channels (VDACs), which are located at the outer mitochondrial membrane (OMM). This transport is regulated with chaperones and regulatory proteins which control the formation of the ER–mitochondria junction. Transfer of calcium from ER to mitochondria depends on high concentration of calcium in the intermembrane space, and mitochondrial calcium uniporter (MCU) accumulates calcium into the mitochondrial matrix for electrochemical gradient. [1]
Transport of phosphatidylserine into mitochondria from the ER for decarboxylation to phosphatidylethanolamine through the ER-mitochondria lipid which transform phosphatidic acid (PA) into phosphatidylserine (PS) by phosphatidylserine synthases 1 and 2 (PSS1, PSS2) in the ER and then transfers PS to mitochondria, where phosphatidylserine decarboxylase (PSD) transform into phosphatidylethanolamine (PE). PE which is synthesized at mitochondria goes back to ER where phosphatidylethanolamine methyltransferase 2 (PEMT2) synthesizes PC (phosphatidylcholine). [2]
The formation of autophagosomes through the coordination of ATG (autophagy-related) proteins and the vesicular trafficking by MAM.[ citation needed ]
These contact sites have been associated with the delicate balance between life and death of the cell. Isolation membranes are the initial step to form auto-phagosomes. These closed membranes are double membrane-bond, with lysosomes inside it. The main function of these membrane is degradation, as role in cellular homeostasis. However, the origin of them has remained unclear. Maybe it is the plasma membrane, the endoplasmic reticulum (ER) and the mitochondria. But the ER- mitochondria contact site have markers, the auto-phagosome marker ATG14, and the auto-phagosome-formation marker ATG5, until the formation of auto-phagosome is complete. Whereas, the absence of ATG14 puncta, it is caused by the breakdown of the ER–mitochondria contact site [3] The oxidative stress and the beginning of endoplasmic reticulum (ER) stress occur together; the ER stress have a key sensor enriched at the mitochondria-associated ER membranes (MAMs). This key is PERK (RNA-dependent protein kinase (PKR)-like ER kinase), PERK contributes to apoptosis twofold by sustaining the levels of pro-apoptotic C/EBP homologous protein (CHOP). [4] A tight ER–mitochondria contact site is integral to the mechanisms controlling cellular apoptosis and to inter-organelle Ca2 + signals. The mitochondria-associated ER membranes (MAMs), play role in cell death modulation. Mitochondrial outer membrane permeabilization (MOMP), is a reason of the higher matrix Ca2 + levels, which is acts as a trigger for apoptosis. MOMP is the process before apoptosis, which is accompanied to permeability of the inner membrane of the mitochondria (IMM). Permeability transition pore (PTP) opening induces mitochondrial swelling and outer membrane of the mitochondria (OMM) rupture. Moreover, PTP opening induce releasing of caspase-activating factors and apoptosis. Caspase-activating factors induced by cytochrome C to bind to the IP3R, this will result in higher Ca2 + transfer from the ER to the mitochondria, amplifying the apoptotic signal. [5]
MAMS play an important role in Ca+2 Homeostasis, phospholipid and cholesterol metabolism. Research has associated the alteration of these functions of MAMs in Alzheimer's disease. [6] Mitochindrial associated membranes associated with Alzheimer's disease have been reported to have an up-regulation of lipids synthesized in the MAMs juxtaposition and an up regulation of protein complexes present in the contact region between the ER and mitochondria. Research has suggested that the sites of MAM are the primary sites of activity for γ-secretase activity and amyloid precursor protein (APP) localization along with the presenilin 1 (PS1), presenilin 2 (PS2) proteins. γ-secretase functions in the cleavage of the beta- APP protein. [5] Patients diagnosed with Alzheimer’s disease have presented results that indicated the accumulation of amyloid beta peptide in the brain which in turn leads to the amyloid cascade suggestion. [7] Also up increased connectivity between the ER and the mitochondria at MAM sites has been observed in human patients diagnosed with familial AD (FAD) by increase of the contact sites. These individuals showed mutations in the PS1, PS2 and APP proteins at the MAM sites. [6] This increased connectivity also caused an abnormality in Ca+2 signaling between neurons. Also with regard to the role in MAMs in phospholipid metabolism, patients diagnosed with AD have been reported to show alterations in levels of Phosphatedylserine and phostphatedylethanolamine in the ER and mitochondria respectively, this leads to the intracellular tangles containing hyperphosphorylated forms of the microtubule‐associated protein tau within tissues. [7]
One of the causes of Parkinson's disease is mutations in genes encoding for different proteins that are localized at the MAM sites. Mutations in the genes that encode the proteins Parkin, PINK1, alpha-Synuclein (α-Syn) or the protein deglycase DJ-1 have been linked to this disease through research. [8] However, further research is still being considered in order to determine the direct correlations of these genes to Parkinson’s disease. In normal conditions, these genes are believed to be responsible for the cells ability to degrade mitochondria that has been rendered nonfunctional in a process known as mitophagy. However, mutations in the Parkin and pink1 genes have been associated with the cells becoming incapable of degrading faulty mitochondria. [9] The proteins alpha-Synuclein (α-Syn) and DJ-1 have been shown to promote MAM function interaction between the ER and the mitochondria. The wild-type gene that codes for α-Syn promotes the physical junction between ER and mitochondria by binding to the lipid raft regions of the MAM. However, the mutant form of this gene has a low affinity to the lipid raft regions, thereby diminishing the contact between the ER and mitochondria and causing accumulation of α-Syn in Lewy bodies which is a major characteristic of PD. [8] Further research on PD association with alterations in MAM is still being developed.[ citation needed ]
Cell biology is a branch of biology that studies the structure, function, and behavior of cells. All living organisms are made of cells. A cell is the basic unit of life that is responsible for the living and functioning of organisms. Cell biology is the study of the structural and functional units of cells. Cell biology encompasses both prokaryotic and eukaryotic cells and has many subtopics which may include the study of cell metabolism, cell communication, cell cycle, biochemistry, and cell composition. The study of cells is performed using several microscopy techniques, cell culture, and cell fractionation. These have allowed for and are currently being used for discoveries and research pertaining to how cells function, ultimately giving insight into understanding larger organisms. Knowing the components of cells and how cells work is fundamental to all biological sciences while also being essential for research in biomedical fields such as cancer, and other diseases. Research in cell biology is interconnected to other fields such as genetics, molecular genetics, molecular biology, medical microbiology, immunology, and cytochemistry.
The endoplasmic reticulum (ER) is, in essence, the transportation system of the eukaryotic cell, and has many other important functions such as protein folding. It is a type of organelle made up of two subunits – rough endoplasmic reticulum (RER), and smooth endoplasmic reticulum (SER). The endoplasmic reticulum is found in most eukaryotic cells and forms an interconnected network of flattened, membrane-enclosed sacs known as cisternae, and tubular structures in the SER. The membranes of the ER are continuous with the outer nuclear membrane. The endoplasmic reticulum is not found in red blood cells, or spermatozoa.
The endomembrane system is composed of the different membranes (endomembranes) that are suspended in the cytoplasm within a eukaryotic cell. These membranes divide the cell into functional and structural compartments, or organelles. In eukaryotes the organelles of the endomembrane system include: the nuclear membrane, the endoplasmic reticulum, the Golgi apparatus, lysosomes, vesicles, endosomes, and plasma (cell) membrane among others. The system is defined more accurately as the set of membranes that forms a single functional and developmental unit, either being connected directly, or exchanging material through vesicle transport. Importantly, the endomembrane system does not include the membranes of plastids or mitochondria, but might have evolved partially from the actions of the latter.
A mitochondrion is an organelle found in the cells of most eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is used throughout the cell as a source of chemical energy. They were discovered by Albert von Kölliker in 1857 in the voluntary muscles of insects. The term mitochondrion was coined by Carl Benda in 1898. The mitochondrion is popularly nicknamed the "powerhouse of the cell", a phrase coined by Philip Siekevitz in a 1957 article of the same name.
Phosphatidylserine is a phospholipid and is a component of the cell membrane. It plays a key role in cell cycle signaling, specifically in relation to apoptosis. It is a key pathway for viruses to enter cells via apoptotic mimicry. Its exposure on the outer surface of a membrane marks the cell for destruction via apoptosis.
Scramblase is a protein responsible for the translocation of phospholipids between the two monolayers of a lipid bilayer of a cell membrane. In humans, phospholipid scramblases (PLSCRs) constitute a family of five homologous proteins that are named as hPLSCR1–hPLSCR5. Scramblases are not members of the general family of transmembrane lipid transporters known as flippases. Scramblases are distinct from flippases and floppases. Scramblases, flippases, and floppases are three different types of enzymatic groups of phospholipid transportation enzymes. The inner-leaflet, facing the inside of the cell, contains negatively charged amino-phospholipids and phosphatidylethanolamine. The outer-leaflet, facing the outside environment, contains phosphatidylcholine and sphingomyelin. Scramblase is an enzyme, present in the cell membrane, that can transport (scramble) the negatively charged phospholipids from the inner-leaflet to the outer-leaflet, and vice versa.
Phosphatidylethanolamine (PE) is a class of phospholipids found in biological membranes. They are synthesized by the addition of cytidine diphosphate-ethanolamine to diglycerides, releasing cytidine monophosphate. S-Adenosyl methionine can subsequently methylate the amine of phosphatidylethanolamines to yield phosphatidylcholines.
The unfolded protein response (UPR) is a cellular stress response related to the endoplasmic reticulum (ER) stress. It has been found to be conserved between mammalian species, as well as yeast and worm organisms.
Mitofusin-2 is a protein that in humans is encoded by the MFN2 gene. Mitofusins are GTPases embedded in the outer membrane of the mitochondria. In mammals MFN1 and MFN2 are essential for mitochondrial fusion. In addition to the mitofusins, OPA1 regulates inner mitochondrial membrane fusion, and DRP1 is responsible for mitochondrial fission.
Mitochondrial fission 1 protein (FIS1) is a protein that in humans is encoded by the FIS1 gene on chromosome 7. This protein is a component of a mitochondrial complex, the ARCosome, that promotes mitochondrial fission. Its role in mitochondrial fission thus implicates it in the regulation of mitochondrial morphology, the cell cycle, and apoptosis. By extension, the protein is involved in associated diseases, including neurodegenerative diseases and cancers.
Brain mitochondrial carrier protein 1 is a protein that in humans is encoded by the SLC25A14 gene.
Membrane contact sites (MCS) are close appositions between two organelles. Ultrastructural studies typically reveal an intermembrane distance in the order of the size of a single protein, as small as 10 nm or wider, with no clear upper limit. These zones of apposition are highly conserved in evolution. These sites are thought to be important to facilitate signalling, and they promote the passage of small molecules, including ions, lipids and reactive oxygen species. MCS are important in the function of the endoplasmic reticulum (ER), since this is the major site of lipid synthesis within cells. The ER makes close contact with many organelles, including mitochondria, Golgi, endosomes, lysosomes, peroxisomes, chloroplasts and the plasma membrane. Both mitochondria and sorting endosomes undergo major rearrangements leading to fission where they contact the ER. Sites of close apposition can also form between most of these organelles most pairwise combinations. First mentions of these contact sites can be found in papers published in the late 1950s mainly visualized using electron microscopy (EM) techniques. Copeland and Dalton described them as “highly specialized tubular form of endoplasmic reticulum in association with the mitochondria and apparently in turn, with the vascular border of the cell”.
Mitochondrial fission is the process where mitochondria divide or segregate into two separate mitochondrial organelles. Mitochondrial fission is counteracted by the process of mitochondrial fusion, whereby two separate mitochondria can fuse together to form a large one. Mitochondrial fusion in turn can result in elongated mitochondrial networks. Both mitochondrial fission and fusion are balanced in the cell, and mutations interfering with either processes are associated with a variety of diseases. Mitochondria can divide by prokaryotic binary fission and since they require mitochondrial DNA for their function, fission is coordinated with DNA replication. Some of the proteins that are involved in mitochondrial fission have been identified and some of them are associated with mitochondrial diseases. Mitochondrial fission has significant implications in stress response and apoptosis.
Histidine triad nucleotide binding protein 2 (HINT2) is a mitochondrial protein that in humans is encoded by the HINT2 gene on chromosome 9. This protein is an AMP-lysine hydrolase and phosphoamidase and may contribute to tumor suppression.
Blarcamesine is an experimental drug developed by Anavex Life Sciences.
The ion channel hypothesis of Alzheimer’s disease (AD), also known as the channel hypothesis or the amyloid beta ion channel hypothesis, is a more recent variant of the amyloid hypothesis of AD, which identifies amyloid beta (Aβ) as the underlying cause of neurotoxicity seen in AD. While the traditional formulation of the amyloid hypothesis pinpoints insoluble, fibrillar aggregates of Aβ as the basis of disruption of calcium ion homeostasis and subsequent apoptosis in AD, the ion channel hypothesis in 1993 introduced the possibility of an ion-channel-forming oligomer of soluble, non-fibrillar Aβ as the cytotoxic species allowing unregulated calcium influx into neurons in AD.
The endoplasmic reticulum membrane protein complex (EMC) is a putative endoplasmic reticulum-resident membrane protein (co-)chaperone. The EMC is evolutionarily conserved in eukaryotes, and its initial appearance might reach back to the last eukaryotic common ancestor (LECA). Many aspects of mEMC biology and molecular function remain to be studied.
Solute carrier family 25 member 46 is a protein that in humans is encoded by the SLC25A46 gene. This protein is a member of the SLC25 mitochondrial solute carrier family. It is a transmembrane protein located in the mitochondrial outer membrane involved in lipid transfer from the endoplasmic reticulum (ER) to mitochondria. Mutations in this gene result in neuropathy and optic atrophy.
GRAM domain containing 1C also known as Aster-C is a cholesterol transport protein that is encoded by the GRAMD1C gene. It contains a transmembrane region, a GRAM domain and a VASt domain. It is anchored to the endoplasmic reticulum through its transmembrane domain.
Jean Vance is a British-Canadian biochemist. She is known for her pioneering work on subcellular organelles and for her discovery of a connection between the endoplasmic reticulum and the mitochondrial membrane. She is a Professor of Medicine at the University of Alberta, Canada and a Fellow of the Royal Society of Canada.
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