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
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]
Regulation of lipid metabolism
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]
Regulation of the morphology: Dynamics and functions of mitochondria, and cell survival
Models of the role of contacts between mitochondria and ER in apoptosis
These membrane 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]
Alzheimer’s disease (AD)
MAMS play an important role in Ca+2
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]
Parkinson's disease (PD)
One of the causes of
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
