Introduction ribosomes from interface showed that specialized ER

Introduction

Eukaryotic cells have membrane bound organelles
that play important role in proper functioning of cells. Understanding of
interorganelle communication is very important because physiology of cell
depend upon contact sites. Largest membrane bound organelle present in
eukaryotic cell is Endoplasmic reticulum (ER). ER performs essential cellular
functions like processing and synthesis of protein, Ca2+ storage and
release, and synthesis of lipid. These organelles have abilities to make
junctions like ER tubular network spread and branched throughout the cytosol these
tubular network form contact site with many organelles present in cells and with
the plasma membrane. One of the example of these contact is ER and
mitochondria. Electron microscopists work for decade and they showed that these
organelles have physical connection (Robertson, 1960; Mannella et al., 1998). At
membrane contact site one feature observed is that ribosomes are absent at
interface of ER and partner organelle. Absence of ribosomes from interface
showed that specialized ER proteins are present that maintain contact sites
(West et al., 2011). Recently protein
complex was identified that play a role in tethering between ER and
mitochondria. This protein complex is referred as Endoplasmic reticulum-
mitochondria encounter structure (ERMES). Multi subunit Protein complex are
situated at interface of these two organelles that helps to zip them together
(Kornmann et al., 2009).  Different
studies indicated that ERMES have role in different processes of cells, like
inheritance and motility of mitochondria, replication of mitochondrial genome,
maintaining phospholipid homeostasis in mitochondria and protein import to
mitochondria (Boldogh et al., 2003; Hobbs et al., 2001; Kornmann et al., 2009;
Osman et al., 2009). Other tether in yeast also discovered such as ER membrane
protein complex (EMC) and mitochondrion vacuole tether. To maintain the typical
distance of 15-30 nm between ER and mitochondrial membrane of mammals under
resting condition is due to tethering proteins presents at the interface of
these two organelles.

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Molecular
Structure of ERMES

ERMES comprises
of five proteins (AhYoung et al.,
2017), Mdm12 (mitochondrial
distribution and morphology protein 12) is a protein present in cytosol. Mmm1
(maintenance of mitochondrial morphology protein 1) is integral membrane
protein of ER and Mdm34/Mdm10 are outer mitochondrial integral membrane
protein. In addition to these proteins calcium binding regulatory GTPase Gem1
is also outer mitochondrial membrane protein, this protein regulates the
function, size and numbers of ERMES complexes in yeast (Kornmann et al., 2011; Murley et al., 2013). ERMES structure analysis
demonstrated that three proteins Mdm12, Mdm34 and Mmm1 share synaptotagmin-like
mitochondrial-lipid-binding protein (SMP) domain and sequences of SMP domain
are not similar (Kopec et al., 2010).
Proteins that have SMP domains are localized at ER and other organelles contact
sites. These proteins are members of the tubular lipid-binding protein (TULIP)
superfamily. Mdm10 is a member of eukaryotic porin superfamily. Mdm10 is core
component of ERMES like Mdm12.

SMP
Domain

SMP
structural studies showed that it exists in dimer form (Beamer et al., 1997). ERMES component assembled
by interaction of SMP domains of these proteins. Many previous studies
indicated that SMP domain spans the entire sequence of Mdm12 protein. Mmm1
comprise of a transmembrane domain that anchor this protein to ER membrane (Jeong et al., 2017). In Mmm1 SMP
domain spans the half of C terminus and localized in cytosol, in Mdm34 SMP
domain comprise half of N terminus followed by region that anchor it to the
outer mitochondrial membrane. The remaining halves of these two proteins are
not conserved between species. SMP domain of Mdm12 and Mmm1 protein assemble
form hetero-tetramer and generate curved shape with ~210 × 45 × 35 A dimension.
Mdm12 basically bridges the two proteins Mmm1 and Mdm34. Many studies showed
that Mdm12 and Mdm34 interact with each other through head- head contact of SMP
domain present in these proteins and Mdm12 interact with Mmm1 through tail to tail
interaction of SMP domains.

Role
of ERMES in Yeast physiology

1.Phospholipid
transport

Primary
role of ERMES in yeast is tether formation. ERMES brings the membrane of two
organelles close to each other at proximity of 10-30nm (Kornmann et al., 2009).  ERMES complex also play role in lipid
trafficking. This indicates that ER mitochondrial junction is necessary for
exchange of phospholipid. phosphatidylserine decarboxylase Psd1 is enzyme
present in mitochondria and necessary for biosynthesis of aminoglycerophospholipid.
For synthesis of phospholipids reactant came from ER and product is returned
back to ER (Achleitner et al., 1999).

Previous
studies showed that when ERMES mutated this slow down the process of metabolic
exchange between ER and mitochondria. Further studies indicate that
mitochondrial membrane of ERMES mutants is not different in lipid composition
as compared to wild type. cardiolipin phosphatidylethanolamine and cardiolipin
were in lower amount in mitochondrial membrane of ERMES mutants, other
phospholipids like phosphatidylcholines or phosphatidylinositols amount in
membrane layer were remain unchanged (Osman et
al., 2009). This perception simply showed that some pathways that are
independent of ERMES also exist in cells. These pathways involve some
transporter proteins like CERT and the OSBP (D’Angelo et al., 2008). These proteins help in maintaining the lipid
homeostasis of mitochondria. The vCLAMP provides another pathway for lipid transferring
from vacuoles to mitochondria (Hönsche et al., 2014; Elbaz-Alon et al., 2014).
If any composite defect found in
these pathways this disrupt the lipid homeostasis of mitochondria.

2.Maintenance of
mitochondrial morphology

Additionally, another important role
played by Mdm12 and Mmm1 complex is in assembly of b-barrel in outer
mitochondrial membrane, in mitochondrial DNA maintenance and mitochondrial
morphology (Kornmann and Walter 2010; Meisinger et al., 2007). Gem1 contain two
EF hand domain and Rho like GTPase domain. Mutation in Gem1 affect the
inheritance and motility of mitochondria.

3.Ca2+ crosstalk
between ER and mitochondria

ER
mitochondria contact site play role in crosstalk of Ca2+. Many
techniques have shown that calcium ions are released from ER are taken up by
mitochondria. This calcium ion uptake by mitochondria is necessary to regulate
mitochondrial activity. When mitochondrial matrix is exposed to Ca2+ to
longer time this results in opening of PTP, cytochrome c released and apoptosis
(Pinton et al., 2008). Mitochondrial transporters have low affinity to Ca2+,
they require high calcium ion concentration for efficient uptake. For this ER-
mitochondrial tether is best site for Calcium ion crosstalk because membrane of
these two organelles are in close proximity (Rizzuto et al., 2004).  ER- mitochondrial tether mediated by ERMES.

4.
Protein import 

Mdm10, an
important protein of ERMES complex. Mdm10 also have regulatory interaction with
sorting and assembly machinery (SAM) complex. 
SAM complex usually influences the assembles of b-barrel protein in
outer mitochondrial membrane. It usually helps in the assembly of Tom40
protein. MDM10 deletion affect the proper
assembly of OMM beta barrel proteins. This observation indicates that the role
of Mdm10 with SAM is regulatory (Kornmann and Walter, 2010).

5.
Replication of mitochondrial genome

mtDNA form
compact structure known as nucleoid. ERMES complex is present close contact
with mtDNA. Yeast that have mutation in ERMES shows defect in maintenance of
mitochondrial genome and lose in mtDNA. This indicated ERMES plays important
role in mitochondrial genome replication.

Mammalian
Tethering proteins of ER and Mitochondria

From previous studies we came to know
that tethering between mitochondria and ER is necessary for normal
physiological processes such as formation of autophagosome, lipid synthesis and
its trafficking, synthesis and distribution of mtDNA. In metazoans, many
proteins and complexes present at ER-mitochondria interference to make tether.
These tethering includes interaction between inositol triphosphate receptor
(IP3R) on ER with voltage gated calcium channel (VDAC) present on mitochondria
via glucose regulated protein 75 (GRP75). GRP 75 is cytosolic chaperon (Szabadkai et al., 2006), interaction of Mfn2 from ER with Mfn2 /Mfn1 on
mitochondria (De Brito &
Scorrano, 2008), Mitochondrial fission 1 homology (Fis1) interact with B cell
receptor associated protein 31 (Bap1) and help in ER- mitochondrial tethering
and induce apoptosis (Iwasawa et al.,
2011). Connection between tyrosine phosphatase interacting protein 51 (PTPIP51)
and vesicle associated membrane protein associated protein B (VAPB) also helps
in ER and mitochondrial tethering and calcium homeostasis (De Vos et al.,
2012).  When these proteins knockout then
interaction between ER and mitochondria reduced and Ca2+ exchange
between two organelles also decreases.

 Recently SMP domain containing protein
discovered in metazoans which is known as PDZ domain containing 8 (PDZD8). This
protein is identified as mammalian ERMES in 2017 by Hirabayashi et al by using
resent bioinformatic approaches. In metazoans, no ERMES ortholog identified
before this study because low amino acid homology sequence was used. This PDZD8
protein is functionally and structurally orthologous to Mmm1 protein present in
ERMEs complex of yeast. Both PDZD8 and Mmm1 contain an N-terminal transmembrane
domain. Next to this domain is SMP domain. In PDZD8 additional domains are
present at C terminus, including PDZ, C1 and CC (coiled coil) domains. Hirabayashi
et al predicted that SMP domains of Mmm1 and PDZD8 shows structural homology
with E-syt2 and Mdm12 SMP domains. To confirm that this protein is orthologous
with Mmm1 of ERMES, expression of chimeric protein (yeast Mmm1 and mouse PDZD8)
in yeast have mutation in MMM1 gene recover the ER mitochondrial contact. This
indicates that PDZD8 had SMP domain that shows functional similarity to one of
protein of yeast ERMES complex. This protein localized in ER at ER-mitochondrial
contact site because PDZD8 was present in MAM fraction and absent in pure
fraction of mitochondria. Loss of PDZD8 in mammalian cells significantly reduce
ER-  mitochondria contact.

ERMES in mammalian physiology

PDZD8 helps in tethering between ER and mitochondria. This
tethering helps in maintaining calcium ion homeostasis. When calcium release
from ER it was taken up by mitochondria. When this tether between ER and
mitochondria absent then this increase the calcium ion concentration in cytosol
rather than in matrix of mitochondria this suggest that the PDZD8 plays
important role in synaptic signaling. Disruption of ER mitochondrial tethering results
in many diseases like Alzheimer’s disease, and amyotrophic lateral sclerosis and
Parkinson’s disease (PD). Discovery of this protein provide new sight to
understand ER-mitochondrial interaction in better way.

Human diseases due to defect in ER and
mitochondrial tethering proteins

            Large amount of energy
is required by neuronal cells for normal activity of cells. Survival of neuron
depend upon morphology and distribution of mitochondria. Alzheimer’s disease is
neurodegenerative disease tied to MAM. In this disease mutation occur in
Presenilin 2 (PS2) (Zampese et al.,
2011). PS2 is required for oxygen consumption at normal level and maintenance
of potential of mitochondrial membrane. 
PS2 mutation leads to increase transfer of calcium from ER to mitochondria,
so calcium ion concentration decreases in ER. A? – Alzheimer’s patients shows
increase expression of Drp1, protein which involves in fission of
mitochondria. 

            Another degenerative
disorder is PD. It has influence on central nervous system usually those cells
that involve in release of Dopamine. In PD loss of function mutation in PINK1
and Parkin results in mitochondrial fragmentation. This fragmentation is
catalyzed by Drp1. Change in number of mitochondria indicate that cell is under
stress.

            Similarly, knockdown of
PDZD8 disturb the Ca2+ uptake by mitochondria, so this protein also
linked with neurodegenerative diseases.

Conclusion:

Tethering proteins are important for normal cell physiology. Any
mutation in genes of these tethering protein associated with diseases.
Discovery of PDZD8 provides a new tool to explain ER-mitochondria tether. Study
at molecular level helps to cure many diseases.