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 Calcium metabolism is the movement and regulation of calcium ions (Ca2+) ''in'' (via the gut) and ''out'' (via the gut and kidneys) of the body, and ''between'' body compartments: the blood plasma, the extracellular and intracellular fluids, and ...

, mitochondrial function, autophagy and apoptosis. They also play a role in development of neurodegenerative diseases and glucose homeostasis.

Role

In mammalian cells, formation of these linkage sites are important for some cellular events including:

Calcium homeostasis

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 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 use ...

(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 The mitochondrial calcium uniporter (MCU) is a transmembrane protein that allows the passage of calcium ions from a cell's cytosol into mitochondria. Its activity is regulated by MICU1 and MICU2, which together with the MCU make up the mitocho ...

(MCU) accumulates calcium into the mitochondrial matrix for electrochemical gradient.

Regulation of lipid metabolism

Transport of

phosphatidylserine Phosphatidylserine (abbreviated Ptd-L-Ser or PS) 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 ap ...

into mitochondria from the ER for decarboxylation to

phosphatidylethanolamine 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 ...

through the ER-mitochondria lipid which transform

phosphatidic acid Phosphatidic acids are anionic phospholipids important to cell signaling and direct activation of lipid-gated ion channels. Hydrolysis of phosphatidic acid gives rise to one molecule each of glycerol and phosphoric acid and two molecules of fatty ac ...

(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).

Regulation of autophagy and
mitophagy Mitophagy is the selective degradation of mitochondria by autophagy. It often occurs to defective mitochondria following damage or stress. The process of mitophagy was first described over a hundred years ago by Margaret Reed Lewis and Warren Harmo ...

The formation of

autophagosome An autophagosome is a spherical structure with double layer membranes. It is the key structure in macroautophagy, the intracellular degradation system for cytoplasmic contents (e.g., abnormal intracellular proteins, excess or damaged organelles, i ...

s through the coordination of ATG (autophagy-related) proteins and the

vesicular trafficking Membrane vesicle trafficking in eukaryotic animal cells involves movement of biochemical signal molecules from synthesis-and-packaging locations in the Golgi body to specific release locations on the inside of the plasma membrane of the secretory ...

by MAM.

Regulation of the morphology: Dynamics and functions of mitochondria, and cell survival

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

lysosome A lysosome () is a membrane-bound organelle found in many animal cells. They are spherical vesicles that contain hydrolytic enzymes that can break down many kinds of biomolecules. A lysosome has a specific composition, of both its membrane pr ...

s 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 absent of ATG14 puncta, it is caused by the breakdown of the ER–mitochondria contact site The

oxidative stress Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage. Disturbances in the normal ...

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). 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.

Alzheimer’s disease (AD)

MAMS play an important role in Ca+2

Homeostasis In biology, homeostasis (British also homoeostasis) (/hɒmɪə(ʊ)ˈsteɪsɪs/) is the state of steady internal, physical, and chemical conditions maintained by living systems. This is the condition of optimal functioning for the organism and ...

, phospholipid and cholesterol metabolism. Research has associated the alteration of these functions of MAMs in Alzheimer's disease. 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 Amyloid-beta precursor protein (APP) is an integral membrane protein expressed in many tissues and concentrated in the synapses of neurons. It functions as a cell surface receptor and has been implicated as a regulator of synapse format ...

(APP) localization along with the presenilin 1 (PS1), presenilin 2 (PS2) proteins. γ-secretase functions in the cleavage of the beta- APP protein. 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. 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. This increased connectivity also caused an abnormality in Ca+2 signaling between

neuron A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. ...

s. 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.

Parkinson's disease (PD)

One of the causes of

Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms becom ...

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 PTEN-induced kinase 1 (PINK1) is a mitochondrial serine/threonine-protein kinase encoded by the ''PINK1'' gene. It is thought to protect cells from stress-induced mitochondrial dysfunction. PINK1 activity causes the parkin protein to bind to d ...

alpha-Synuclein Alpha-synuclein is a protein that, in humans, is encoded by the ''SNCA'' gene. Alpha-synuclein is a neuronal protein that regulates synaptic vesicle trafficking and subsequent neurotransmitter release. It is abundant in the brain, while smaller a ...

(α-Syn) or the protein deglycase DJ-1 have been linked to this disease through research. 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 Mitophagy is the selective degradation of mitochondria by autophagy. It often occurs to defective mitochondria following damage or stress. The process of mitophagy was first described over a hundred years ago by Margaret Reed Lewis and Warren Harmo ...

. However, mutations in the Parkin and pink1 genes have been associated with the cells becoming incapable of degrading faulty mitochondria. 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 The plasma membranes of cells contain combinations of glycosphingolipids, cholesterol and protein receptors organised in glycolipoprotein lipid microdomains termed lipid rafts. Their existence in cellular membranes remains somewhat controversial ...

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. Further research on PD association with alterations in MAM is still being developed.

References

{{Reflist Neurodegenerative disorders Cell biology Mitochondria Membrane biology