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ER–mitochondria contact sites in yeast: beyond the
myths of ERMES
Alexander Lang, Arun T John Peter and Benoı̂t Kornmann
A standout feature of eukaryotic cells is the presence of
organelles with distinct chemical compositions and physical
properties, which aid in the accomplishment of specialized
metabolic tasks. This complex topology, however, makes a
permanent crosstalk between the organelles a necessity for the
coordination of cellular function. While molecule exchange
between organelles via the vesicular transport system has been
extensively studied, communication via direct connections has
only recently become a new matter of interest. These direct
connections termed membrane contact sites (MCSs) represent
zones of close proximity (10–30 nm) between two organelles.
Research in the past years has revealed a number of MCSs
especially between the ER and almost every other organelle
[1]. In particular, the MCSs between the ER and the
mitochondria have undergone intense investigation. While the
quest for ER–mitochondria MCS components in human cells
has led to the revelation of an ever growing number of potential
factors, studies in the simpler eukaryote Saccharomyces
cerevisiae revealed the actual existence of a molecular tether
between the two organelles [2].
Address
Institute of Biochemistry, ETH Zurich, 8093 Zürich, Switzerland
Corresponding author: Kornmann, Benoı̂t
([email protected])
Current Opinion in Cell Biology 2015, 35:7–12
This review comes from a themed issue on Cell organelles
Edited by Maya Schuldiner and Wei Guo
http://dx.doi.org/10.1016/j.ceb.2015.03.002
0955-0674/# 2015 Elsevier Ltd. All right reserved.
which encode two subunits of a same complex. Further
experiments showed that this complex was made of an
ER membrane protein (Mmm1), two outer mitochondrial
membrane proteins (Mdm10, Mdm34) and a cytosolic
protein (Mdm12), which come together at ER–mitochondria interfaces, to form a molecular bridge between the
two organelles (Figure 1d). In addition to the four core
components, the mitochondrial Rho-like GTPase Gem1
is thought to be a facultative regulatory subunit of the
ERMES complex [3,4]. The remarkable subcellular localization of the ERMES complex, and the fact that some
of its components can be replaced by an artificial tether,
suggested that one preeminent role of the ERMES
complex was to provide tethering force between the
two organelles. As we will see, the truth may however
be more complex. ERMES mutants are known to manifest defective mitochondrial morphology, mtDNA maintenance, mitochondrial protein import and growth,
especially on non-fermentable media [5–11].
The discovery of the ERMES complex thus laid foundations to understand how mitochondria, excluded from
vesicular traffic routes, might communicate with other
organelles, and to explore the molecular basis of interorganelle communication in general. In this background,
it seemed that the only major quest left was to define the
nature of the metabolites and the mechanisms of their
exchange between the ER and the mitochondria. In
contrast to this idea, a number of fascinating studies have
revealed unexpected roles for ERMES in mitochondrial
biology including mitochondrial dynamics, inheritance,
protein import, mtDNA inheritance and mitophagy
[12,13,14]. Given this diversity, it has become difficult
to differentiate between the direct and indirect functions
of the ERMES complex, leading to much confusion. In an
attempt to make sense out of it, we discuss the different
functions of the ERMES complex and try to weigh the
available evidence.
Introduction
Lipids — obvious, controversial, confusing
The ER–mitochondria encounter structure (ERMES)
was originally discovered using a genetic screen based
on the following hypothesis: impairing ER–mitochondria
tethering proteins might yield a lethal phenotype, but this
lethality should be reversed if an artificial tethering
activity could compensate for the loss of the endogenous
one. Specifically, we screened for mutants incapable of
growing if they did not express a synthetic protein
designed to tether the ER to the mitochondria. This
approach identified two genes (MDM12 and MDM34),
In yeast, the ER and mitochondria share the task to
synthesize glycerophospholipids. In this process, phosphatidylserine (PS) synthesized in the ER membrane, is
transported to the mitochondria where it is converted to
phosphatidylethanolamine (PE) by the PS decarboxylase
(Psd1), which resides in the inner mitochondrial membrane
(IMM) [15]. PE is then shuttled back to the ER, where
specific enzymes convert it to phosphatidylcholine (PC),
the most abundant phospholipid in yeast membranes.
Since mitochondria are apart from vesicular transport,
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Current Opinion in Cell Biology 2015, 35:7–12
8 Cell organelles
Figure 1
(a)
(b)
(c)
(d)
45º
Mdm12
45º
60º
OMM
Mmm1
45º
Mmm1
45º
Mdm34
Mdm10
60º
ER
Current Opinion in Cell Biology
(a) The lipid-binding SMP domain of E-Syt2 (Adapted from [20]). Two hydrophobic molecules are shown in red. One is a phospholipid; the other
is a detergent molecule, occupying a pocket that presumably binds a second phospholipid in vivo. Hydrophobic amino acids coating the lipidbinding groove are shown in blue. (b) As in (a) except that the green part in (a) has been removed to expose the lipid binding groove. (c) Two
SMP domains of E-Syt2 dimerize to form an elongated hydrophobic conduit. (d) Speculative model for how the SMP domains of ERMES
components interact as dimers to allow lipid exchange between the ER and the OMM. This model might explain why an artificial tether can rescue
the loss of Mdm12 or Mdm34: while both proteins are needed to form a stable complex, the absence of either one of them can be compensated
for by the expression of an artificial tether. This ectopic force may allow the remaining components to assemble as a complex, which is functional
in lipid exchange owing to the redundancy of Mdm12 and Mdm34 SMP domains.
the routes that lipids use to reach the mitochondrial membranes have remained mysterious, and ER–mitochondria
MCSs have long been proposed to play a role in this process
[16,17]. Being the ER–mitochondria tether, an obvious
question that arises is whether the ERMES complex participates in the shuttling of lipids between the two organelles. A number of observations support this idea. First of
all, an unbiased genetic interaction screen revealed a strong
phenotypical correlation between every ERMES subunit
and Psd1, indicating that they are functionally linked
towards the generation of PE [2]. Next, three of four
core ERMES subunits harbor the conserved SMP (Synapdototagmin-like-Mitochondrial-PhD/Pdz-associated)
main, which, by virtue of its similarity to the TULIP
(tubular lipid-binding) domain, has been suggested to bind
lipids [18,19]. Indeed, this prediction has been experimentally confirmed with the recently solved crystal structure of the SMP domain of the mammalian extended
synaptotagmin E-Syt2 [20] (Figure 1a–c). Strikingly,
the SMP domains of E-Syt2 dimerize and bind phospholipids in a hydrophobic cavity, extracting and isolating it
from its original bilayer. Therefore, it is tempting to speculate that ERMES subunits could act in a similar fashion,
potentially catalyzing the ‘sliding’ of phospholipids between the ER and mitochondria (Figure 1d).
Current Opinion in Cell Biology 2015, 35:7–12
However obvious the above evidence may seem, the fact
remains that yeast cells harbor at least partially functional
mitochondria in the absence of ERMES complex, refuting the idea of ERMES as the sole mediator of lipid
exchange between ER and mitochondria. In fact, cells
lacking a functional ERMES complex lose only partly
their ability to convert PS to PC and the total lipid
composition of the cell is only marginally affected
[2,21]. To make this conundrum more formidable,
Nguyen et al. published that the deletion of ERMES
subunits had no effect on PS to PE conversion [22].
Finally, yet another complication arises from the fact that
an artificial protein construct designed solely to tether the
ER and mitochondria, rescues the phenotypes caused by
the absence of Mdm12 or Mdm34, two of the three
ERMES components that bear an SMP domain [2].
How can a mere tether, unable to bind or transport lipids,
compensate for the loss of probable lipid exchange catalysts? This conundrum can only be resolved if we assume
that these ERMES subunits are redundant for lipid
exchange but not for tethering (Figure 1d).
Taken together, it is clear that the mechanisms that govern
lipid flow to the mitochondria are not straightforward and
cells might have evolved complicated mechanisms to
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ERMES and ER–mitochondria contact sites Lang, John Peter and Kornmann 9
compensate for the loss of ERMES function in maintaining mitochondrial homeostasis. Indeed, to illustrate the
complexity involved, two groups have independently
discovered a contact site between the mitochondria and
vacuole, named vCLAMP (vacuole and mitochondria
patch), which may represent an alternative route to deliver
lipids to the mitochondria [23,24]. It is known that the
vacuole and the ER maintain direct contacts via the
nucleus–vacuole junctions (NVJs) [25]. Therefore, it is
possible that, in the absence of ERMES, ER communicates with the mitochondrion indirectly with the aid of
NVJs and vCLAMPs. Though the molecular composition
of vCLAMP remains incomplete, the vacuolar component
is Vps39, a protein that is also part of the vacuole fusion
machinery. Intriguingly, the authors observe strong lipid
homeostasis defects in a mutant defective for both
ERMES and vCLAMP, suggesting that these two tethering complexes compensate for each other. Moreover,
impairing ERMES leads to an increase in vCLAMPs
and vice versa, hinting to a regulatory connection between
both structures, in addition to the functional one [24].
Furthermore, yet another recent study has unraveled a
second ER–mitochondria tether termed the ER–membrane protein complex (EMC) [26]. The complex consists
of six subunits, named Emc1–6, that localize to both the
peripheral and nuclear ER and interacts with the outer
mitochondrial membrane protein Tom5. Interestingly, the
authors find that the conversion of PS to PE is impaired
only upon loss of multiple subunits of this complex, suggesting that the EMC proteins can both work together in
the EMC complex, and in a parallel redundant way, when
the complex is disrupted. Strikingly, the foci where Emc1
and its mitochondrial partner Tom5 interact co-localize
with the ERMES foci, suggesting that ERMES may support the function of EMC. It is notable that an artificial ER–
mitochondria tether also co-localizes with ERMES foci
[2] indicating that the contact sites between ER and
mitochondria might involve ERMES by default.
Apart from these protein complexes, over-expression of
two mitochondrial proteins MCP1 and MCP2, restores
normal growth and steady state levels of mitochondrial
phospholipids in Mdm10-deficient cells [27]. Intriguingly, the authors also find elevated levels of ergosterol in
cells lacking Mdm10, Mmm1 or Mdm12, which are
restored to normal levels upon MCP1 or MCP2 overexpression. How ERMES and Mcp1/2 proteins impact
ergosterol levels is unknown. It is notable, however, that
Mcp2 is a member of an ATPase family involved in the
biosynthesis of isoprenoid lipids [28], which may explain
its effect on ergosterol levels. It is also possible that these
changes could be secondary to changes in phospholipid
homeostasis. In addition, ER-shaping factors like the
reticulons have been implicated in ERMES-mediated
lipid exchange. This observation suggests that the lipid-transport capability of ERMES somehow relies on a
correctly-shaped and operative ER [29].
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Taken together, the described findings reflect that we are
only beginning to understand the complex pathways of
lipid homeostasis, which, without a doubt, deserve further
investigation.
Protein import
To complicate the topic even further, Mdm10, the only bbarrel protein in the ERMES complex, has been described to act together with the Sorting and Assembly
Machinery (SAM), a complex required to integrate bbarrel proteins into the outer mitochondrial membrane
(OMM) after their import via the TOM complex [30]. In
this context, the model from 2010 by Yamano
et al. [13,31] that suggests Mdm10 to be a dynamic
constituent of both ERMES and the SAM machinery
raises an important question. Are the phenotypes observed upon ERMES deficiency due to a defect in the
assembly of b-barrel proteins on the OMM? As mentioned earlier, the over-expression of the mitochondrial
proteins, MCP1 and MCP2, which rescues most MDM10
deletion-associated phenotypes, does not rescue the function of Mdm10 in b-barrel protein assembly [27]. This
observation indicates that ERMES-associated phenotypes are not secondary effects that result from a defective SAM machinery. Why a single protein is part of two
different complexes with such seemingly different functions remains to be explored.
Mitochondrial dynamics and inheritance
All genes encoding core ERMES component are called
either MDM (for mitochondria distribution and morphology) [5,6,8] or MMM (for mitochondria morphology
maintenance) [7] because their mutation impairs the
maintenance of a tubular mitochondrial network, as well
as its transmission to daughter cells. Ball-like and bloated
mitochondria represent the most obvious phenotype associated with ERMES defects. Explanations and possible
mechanisms for this apparently simple behavior fly off in
many different directions, resulting again in a confusing
picture.
In early models Mmm1, Mdm10 and Mdm12 were
thought to form a kinetochore-like complex called mitochore — allowing mitochondria to connect to, and travel
on actin cables [9]. In contradiction to this model, mitochondrial attachment to actin cable was later proposed to
be the product of the interaction either between the yeast
Type V myosin motor 2 (Myo2) and the mitochondrial
Myosin-2 receptor 1 (Mmr1), or between Myo2 and the
Rab protein Ypt11 [32–35]. Eventually, two studies suggested that the mitochondrial inheritance problems associated with ERMES impairments are not due to problems
with mitochondrial motility but rather to a secondary
effect of distorted mitochondrial shape, disconnecting
ERMES and mitochondrial inheritance from each other
[22,36]. It should be noted, that even though none of the
core components of ERMES seem to be directly involved
Current Opinion in Cell Biology 2015, 35:7–12
10 Cell organelles
in actin-based movement, the accessory ERMES component Gem1 shows a synthetic phenotype with the mitochondrial Myo2 receptor machinery, where a strain
harboring the triple deletion gem1D mmr1D ypt11D has
a strong mitochondria inheritance defect [37]. Moreover,
Gem1 is the ortholog of the metazoan protein Miro, which
has an established role in microtubule-based mitochondrial movement [38,39]. Thus, the connection between
ERMES and mitochondrial inheritance still needs to be
clarified.
Furthermore, Gem1 and ERMES were shown to associate with ER-associated Mitochondrial Division (ERMD),
a process in which ER-tubules mark mitochondrial division sites by facilitating the constriction of the mitochondria [12,40] (Figure 2). ERMES not only marks
sites of ERMD but also, together with Gem1, localizes
asymmetrically to only one of the two newly formed
mitochondrial tips. In this process, Gem1 is proposed to
facilitate the separation of the daughter mitochondria
from the ER segment that aided their division. ERMD
events also co-localize with mitochondrial DNA
(mtDNA) containing nucleoids, a condition which might
promote an equal distribution of mtDNA between dividing mitochondria (Figure 2). Moreover, ERMES
members have been shown to be spatially linked to
nucleoids undergoing replication [11,41]. This, and
the finding, that ERMES mutants, including gem1D
[42], lose their mtDNA, suggest a close liaison between
both, but how a protein complex on the cytosolic side of
the mitochondrion connects to the mtDNA in the matrix
remains a mystery.
Mitophagy
Mitophagy represents the selective autophagic turnover
of mitochondria that are either damaged [43], or have
been rendered superfluous by a shift in growth conditions
[44]. Using an assay to induce mitophagy in the presence
of fermentable carbon sources, Böckler et al. have unveiled an unexpected requirement for ERMES during
mitophagy [14]. Intriguingly, ERMES members seem
to co-localize with Atg8, a protein that marks the growing
autophagosome (Figure 2). Furthermore, during mitophagy induction in the absence of ERMES, the accumulation of immature autophagosomes suggests that the
ERMES complex may contribute to lipid supply for
the growing double membrane. Taken together, the
authors conclude that the ERMES-mediated ER–mitochondria tethering might combine the supply of lipids to
the autophagosomal membrane and targeting of mitochondria for degradation.
Discussion
To put the diverse functions of the ERMES members
into perspective, we try to categorize and briefly analyze
the available evidence with a hope to get a picture that
differentiates between the unambiguous and ambiguous
functions of the ERMES complex. The above functions
have all been inferred from very different types of evidence. Some of the evidence is merely related to the
phenotype of yeast strains lacking ERMES. While such
evidence can be very informative to assign a function, it
can also be misleading, as a phenotype may be a direct
consequence of the loss of ERMES, or a secondary
consequence, due to the loss of a primary function. Some
Figure 2
ER
ERMES
PAS
Mitochondrion
Fission Factors
EMC
vCLAMP
Lipid exchange
mtDNA
Vacuole
Current Opinion in Cell Biology
A broad picture of ERMES functions. ERMES participates in lipid exchange between the ER and mitochondria. The vCLAMP and the EMC
complex may be partially redundant for this function. Additionally, ERMES sites are also assembly sites for the mitochondrial fission machinery.
ER-mediated constriction of the mitochondrion may participate in promoting mitochondrial division. ERMES are also sites of pre-autophagosome
assembly for selective mitochondrial autophagy (mitophagy). ERMES co-localizes with the pre-autophagosomal structure (PAS) and the growing
autophagosome. The ER may serve as a source of lipids for the growing autophagosome, although this idea is intensely debated [46,47].
Current Opinion in Cell Biology 2015, 35:7–12
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ERMES and ER–mitochondria contact sites Lang, John Peter and Kornmann 11
of the evidence is based on subcellular localization: two
processes happening at the same location are likely to be
connected directly or indirectly.
A third type of evidence is the biochemical activity of the
proteins themselves. With regard to lipid exchange, the
crystal structure of the SMP domain has given important
insights on the possible activity of ERMES components
and the mechanism by which they might promote lipid
exchange. In further support, the punctate localization of
ERMES members at the ER–mitochondria junction suggests that they are at the right place for the right job.
However, the phenotypic evidence for ERMES-mediated lipid exchange remains weak as mitochondrial membrane biogenesis is only partially affected in ERMES
mutants. Is this due to the compensation by alternative
lipid exchange pathways as suggested by recent studies?
Moreover, if the ERMES complex is responsible for
carrying out such an important and universal task, how
can we explain that the metazoan lineage appears to have
lost ERMES [45]?
The case of mitochondrial dynamics relies pretty much
solely on phenotype-based evidence, except for mitochondrial fission, where excellent microscopy experiments have shown a common localization for ERMES
and ERMD events. However, a role in mitochondrial
dynamics is not easily reconciled with the probable lipid
transport function of ERMES subunits. Does fission
require the ER to provide lipids to the mitochondria to
promote membrane rearrangements necessary for fission?
In mitophagy, ERMES mutants have a strong phenotype
as they were among the best hits in the screen for
mitophagy-deficient mutants. Moreover, ERMES subunits clearly co-localize with components of the autophagic
machinery. What is the logic behind the presence of
probable lipid transporters at sites of mitophagy initiation? Does the autophagosome require lipids found at the
interface of both membranes? Or does the proximity of
the ER and the mitochondria aid the autophagosome,
presumably originating from the ER, to engulf the proper
target? This brief analysis of the literature suggests that
the function of the ERMES complex may have at least
two faces: firstly, as a lipid exchanger and secondly, as a
mechanical tether. Can we separate these functions by,
for instance, blocking the lipid channels in ERMES
components? Apart from lipids and tethering force, are
there other dimensions to the ERMES-mediated hug
between the two organelles? While we don’t have good
answers yet, we are convinced that exciting times are
ahead for the field of ER–mitochondria contact sites.
References and recommended reading
Papers of particular interest, published within the period of review,
have been highlighted as:
of special interest
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