A Biochemical Society held at the Snowbird Ski and Summer Resort, Snowbird, UT, U.S.A., 6–9 October 2011. Organized and Edited by Tim Levine (Institute of
Ophthalmology, London, U.K.) and William Prinz (National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda,
Biochemical Society Transactions
www.biochemsoctrans.org
MD, U.S.A.).
The ERMES complex and ER–mitochondria
connections
Agnès H. Michel and Benoı̂t Kornmann1
Institute of Biochemistry, ETH Zurich, 8093 Zurich, Switzerland
Abstract
Cellular organelles need to communicate in order to co-ordinate homoeostasis of the compartmentalized
eukaryotic cell. Such communication involves the formation of membrane contact sites between adjacent
organelles, allowing privileged exchange of metabolites and information. Using a synthetic protein designed
to artificially tether the ER (endoplasmic reticulum) to mitochondria, we have discovered a yeast protein
complex naturally involved in establishing and maintaining contact sites between these two organelles.
This protein complex is physiologically involved in a plethora of mitochondrial processes, suggesting that
ER–mitochondria connections play a central co-ordinating role in the regulation of mitochondrial biology.
Recent biochemical characterization of this protein complex led to the discovery that GTPases of the Miro
family are part of ER–mitochondria connections. The yeast Miro GTPase Gem1 localizes to ER–mitochondria
interface and influences the size and distribution of mitochondria. Thus Miro GTPases may serve as regulators
of the ER–mitochondria connection.
ER (endoplasmic reticulum)–mitochondria
contact sites
The eukaryotic cell is a highly complex entity that carries
out many distinct functions that are interdependent and
interconnected. Organelles are compartments dedicated to
the realization of specific biochemical tasks that require
an appropriate and controlled milieu. While the compartmentalization of the eukaryotic cell into organelles ensures
that incompatible biochemical pathways remain separated,
it also creates the need for communication routes that
Key words: cardiolipin, cytosol, endoplasmic reticulum (ER), endoplasmic reticulum–
mitochondria encounter structure (ERMES), lipid binding, mitochondrion.
Abbreviations used: CL, cardiolipin; ER, endoplasmic reticulum; ERMES, ER–mitochondria
encounter structures; IMM, inner mitochondrial membrane; IP3 , inositol trisphosphate; Mdm,
mitochondrial distribution and morphology; Mmm1, mitochondrial morphology maintenance
1; mtDNA, mitochondrial DNA; OMM, outer mitochondrial membrane; PE, phosphatidylethanolamine; Psd1, phosphatidylserine decarboxylase 1; SAM, sorting and assembly machinery;
SMP, synaptotagmin-like, mitochondrial and lipid-binding protein; TOM, translocase of the
mitochondrial outer membrane; TULIP, tubular lipid-binding.
1
To whom correspondence should be addressed (email [email protected].
ethz.ch).
Biochem. Soc. Trans. (2012) 40, 445–450; doi:10.1042/BST20110758
allow organelles to exchange the information and metabolites
required to fulfil their function [1,2].
The ER and the mitochondria are two organelles that undergo this type of privileged communication. The membrane
of both organelles can often be observed in close apposition
by electron microscopy. Moreover, isolated subcellular mitochondrial fractions contain contaminating ER membranes [3].
These contaminating ER membranes have a molecular composition that is slightly different from that of the general ER,
suggesting that these mitochondria-associated membranes
represent a laterally differentiated subcompartment of the
ER, which is physically attached to the mitochondria [4].
The physical connection between the ER and mitochondria
might serve different physiological purposes.
The first one is lipid exchange. Mitochondria are enclosed
by a double membrane, the OMM (outer mitochondrial
membrane) and the IMM (inner mitochondrial membrane).
Therefore the mitochondrion is a membrane-rich organelle.
Most phospholipids are synthesized in the ER and distributed
to other organelles via vesicular transport. Mitochondria,
however, are not part of the endomembrane system and
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therefore do not receive phospholipids from the ER via
vesicular trafficking. ER–mitochondria contact sites have
been proposed to favour lipid exchange between both
organelles [4]. Lipid exchange is not only necessary for the
biogenesis of mitochondrial membranes but also for general
lipid synthesis. The decarboxylation of PS (phosphatidylserine) to PE (phosphatidylethanolamine) is carried out by an
enzyme, Psd1 (phosphatidylserine decarboxylase 1), that
resides in the mitochondria, implying that the substrate and
product of the reaction must respectively leave the ER to
reach the mitochondria, and go back to the ER to be further
distributed to other cellular membranes [5].
Another proposed role for the ER–mitochondria connection is to promote interorganelle calcium (Ca2 + ) exchange.
When Ca2 + is released from the ER by the activation
of the IP3 (inositol trisphosphate) receptor, an increase in
Ca2 + concentration ([Ca2 + ]) can be observed both in the
cytosol and in mitochondria [6]. This is surprising because
mitochondria in isolation are only weakly able to take up
Ca2 + , even at the maximum concentrations that can be
attained in the cytosol. This is inconsistent with the idea
that the increase in cytosolic [Ca2 + ] is sufficient to cause
an increase in mitochondrial [Ca2 + ]. A model to explain this
discrepancy proposes that the close apposition of the ER and
the mitochondria creates micro-domains in which [Ca2 + ]
reaches much higher levels than in the rest of the cytosol,
akin to the high neurotransmitter concentration that can be
found at neurological synapses [6].
Many mitochondrial enzymes are Ca2 + -dependent,
therefore Ca2 + signalling within the mitochondria is
critical for the generation of ATP. Moreover, mitochondrial
Ca2 + participates in triggering apoptosis, indicating that
mitochondrial Ca2 + must be tightly regulated [7].
For a long time, proteinaceous factors involved in tethering
the ER and the mitochondria resisted identification. In
recent years, however, many proteins have been shown to
be involved in ER–mitochondria tethering. These include the
ER-resident Ca2 + channel IP3 receptor, the mitochondrial
voltage-dependent anion channel [8], the chaperones grp75
and sigma-1R [9], the sorting protein PACS-2 [10], the fission
factor Fis1, the ER protein Bap31 [11] and the mitofusin Mfn2
[12].
A screen to identify the ER–mitochondria
protein junction
We turned to the simple budding yeast Saccharomyces
cerevisiae and designed a screen aimed at discovering the
bridges that connect the ER to the mitochondria. Inspired by
a study in mammalian cells that used engineered chimaeric
proteins to artificially tether the ER to the mitochondria
[13], we reasoned that artificial ER–mitochondria tethering
might allow the growth of mutants in which endogenous
tethering components were mutated. We created an artificial
ER–mitochondria tether and screened for mutants that could
not grow in the absence of this construct. Two mutations
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MDM12 gene [14].
Mdm (mitochondrial distribution and morphology) 12 is
a peripheral OMM protein identified more than 10 years ago
in a screen for mitochondrial distribution- and morphologydeficient mutants [15]. Mutants defective for Mdm12 grow
poorly on fermentable medium and are totally incapable
of growing on a non-fermentable carbon source [14,15].
These phenotypes are rescued by the expression of the
artificial tether. Mdm12 is embedded in a complex containing
two mitochondrial proteins (Mdm10 and Mdm34) and a
fourth protein called Mmm1 (mitochondrial morphology
maintenance 1) (Figure 1A). This protein was long thought
to be inserted in the OMM. We were able to show that,
despite deceptive appearances, Mmm1 is an ER-integral
protein [14]. All four proteins form stable complexes at the
interface of the ER and the mitochondria, thus zippering
the two organelles. We named this complex ERMES (ER–
mitochondria encounter structures). ERMES forms one
to five discrete focal structures per cell [16] at the ER–
mitochondria interface [14] (Figure 1B).
Physiology of the ER–mitochondria
connection: lipid exchange
As stated above, one role of ER–mitochondria connection is
to facilitate lipid exchange between both organelles [5]. Two
pieces of evidence from the analysis of ERMES corroborate
this model.
The first piece of evidence stems from an unbiased genomescale screen that utilizes genetic interactions to compare
thousands of mutants according to the similarity of their
genetic interaction pattern. Hierarchical clustering allows the
sorting of genes according to their proximity in this analysis.
In the case of ERMES, all four components of the complex
tightly segregated together, demonstrating the power of the
method at detecting functional relationships [14]. In addition,
the cluster contained the GTPase Gem1 (see below) and Psd1.
This latter enzyme is central in the biosynthesis pathway of
PE. While all other PE biosynthesis steps are carried out in
the endomembrane system, Psd1 is an IMM protein, meaning
that both its substrate and products have to come from and
go back to the ER respectively [5], indicating a functional link
between ERMES and ER–mitochondrial lipid exchange.
The second piece of evidence arises from bioinformatic
analyses. Mdm12 is the founding member of the SMP
(synaptotagmin-like, mitochondrial and lipid-binding protein) family of membrane proteins. Both Mdm34 and Mmm1
also contain SMP domains, together with a handful of
conserved eukaryotic proteins [17,18]. Homology searches
using secondary structure-based hidden Markov models
detected a remote resemblance between SMP domains and
a class of lipid-binding proteins [18]. This family of lipidbinding proteins is characterized by its tubular shape and
is called TULIP (tubular lipid-binding). Lipid binding in
the TULIP domain involves an elongated hydrophobic
groove that buries the hydrophobic moieties of bound lipids,
Cellular Traffic of Lipids and Calcium at Membrane Contact Sites
Figure 1 Topology of the ERMES complex at the ER–mitochondria connection
(A) Mmm1 is an ER protein, while Mdm10 is an OMM β-barrel. Mdm12 is a cytosolic protein. Mdm34 is associated with
the OMM through an unclear mechanism. (B) The ERMES complex accumulates in a few discrete foci per cell. Here a green
fluorescent protein (GFP)-tagged version of Mdm34 (green) is imaged together with a marker for the mitochondria (red).
The outlines of the cells are shown as broken lines.
whereas the polar head remains usually mainly accessible to
the aqueous environment (Figure 2B). The similarity between
SMP and TULIP domains suggests a very tempting model
where the SMP domains found in Mdm12, Mdm34 and
Mmm1 directly catalyse lipid exchange between adjacent
membranes at the ER–mitochondria interface [18].
Physiology of the ER–mitochondria
connection: a plethora of other processes
The physiological role of ERMES does not appear limited
to lipid exchange. In fact, ERMES components have been
under heavy scrutiny, long before our discovery of their
involvement in ER–mitochondria connections. These studies
point to a much broader physiological role of ERMES in
mitochondrial biology.
ERMES localizes adjacent to the mtDNA (mitochondrial
DNA), which is arranged in the mitochondria as nucleoids
[19]. Strikingly, ERMES co-localizes specifically with actively
replicating nucleoids, indicating that ERMES may be
involved in the regulation of mtDNA replication [20]. A
physical link between ERMES and mtDNA replication
proteins has even been shown [20], and ERMES mutants
frequently lose mtDNA, indicating a defect in replication or
segregation of the mitochondrial genome [19].
ERMES complexes are also indirectly connected to
mitochondrial protein import. Mdm10 is a central component
of ERMES but a fraction of it can be found as a part of
another complex, the SAM (sorting and assembly machinery),
that assembles β-barrels in the OMM [21]. Mdm10 is
itself a β-barrel protein and competes with other βbarrels for the substrate-binding pocket in the SAM [22].
Mdm10 presence within SAM is especially important for
the assembly of TOM40 (translocase of the mitochondrial
outer membrane 40) [21]. Too little Mdm10 causes TOM40
to remain associated with the SAM complex after its full
assembly. Conversely, too much Mdm10 causes premature
Figure 2 ERMES complexes may exchange lipids between the ER
and the mitochondria
(A) Bioinformatic comparison of the structures of ERMES members show
that three of four canonical ERMES components harbour an SMP domain,
either alone (Mdm12), or in combination with a transmembrane domain
(TM; Mmm1) or a DUF (domain of unknown function; Mdm34). Mdm10
harbours no SMP domain and instead bears characteristics of MOM
(mitochondrial outer membrane) β-barrels. (B) The SMP domain is
related to the TULIP domain. The crystal structure of a TULIP protein,
the human bactericidal permeability-increasing (BPI) protein [35],
shows two phospholipid molecules bound in two pseudo-symmetrical
lipid-binding domains. The lipids have their acyl chain buried within
the protein and their polar head exposed to the solvent (upper panel).
Lower panel displays a 90◦ rotation of the structure, showing that the
lipid-binding groove extends along the length of the protein.
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Figure 3 The Miro GTPase Gem1 is a component of the ERMES complex
(A) Architecture of Miro GTPases: Two GTPase domains flank two Ca2 + -binding domains. The C-terminus anchors the
protein to the OMM. C, C-terminus; Cyt, cytosol; IMS, inter-membrane space; N, N-terminus. (B) Green fluorescent protein
(GFP)-tagged Gem1 is found in focal structures together with mCherry-tagged Mdm34 at the ER–mitochondria interface. The
broken lines represent the outlines of the cells.
displacement of TOM40 from the SAM complex [22].
Mutations in other components of ERMES cause the same
defects in β-barrel assembly as does Mdm10 overexpression
[22,23], suggesting that both complexes compete for a
limiting amount of Mdm10. Although the link between ER–
mitochondria connection and mitochondrial protein import
is unclear, this competition suggests that SAM and ERMES
may regulate each other [24].
Thus it appears that ERMES is found at an important
crossroad of mitochondrial biology, potentially extending its
influence on processes as diverse as membrane biogenesis,
genome replication and protein import. This suggests that
ERMES may be a co-ordinator that ensures that these
processes are performed in harmony for the proper function
of mitochondria [25].
The Miro GTPase Gem1 as a regulator
of ERMES
If ERMES is indeed such a co-ordinator, then it is expected to
sense cellular cues and propagate appropriate responses. This
immediately raises the following question: what regulates
ERMES? We obtained a preliminary answer by characterizing
the ERMES complex biochemically.
Using affinity purification of functional Tap-tagged
versions of Mmm1 and Mdm34, we and another group
purified intact ERMES complexes containing all four known
components [26,27]. In addition, we identified the Miro
GTPase Gem1 as a novel ERMES component. Gem1 colocalizes with ERMES core components in a few foci per
cells [26,27] (Figure 3B).
Miro GTPases are characterized by their unusual
architecture. Two GTPase domains flank two Ca2 + -binding
EF hands. The C-terminus of Miro GTPases constitutes a
hydrophobic tail, which anchors the protein to the OMM
[28] (Figure 3A). This architecture strongly suggests that
Gem1 could play a regulatory role in ERMES biology.
Indeed, contrary to deletions of the canonical ERMES
members, deletion of Gem1 does not compromise complex
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appear larger and in reduced number compared with wildtype counterparts, suggesting that Gem1 influences ERMES
organization [26]. The recruitment of Gem1 to ERMES appears to be itself a regulated process. Mutations that kill
the GTPase activity of the first domain abrogate Gem1
localization to ERMES foci, while mutations in the second
domain do not. The same holds true for mutations of the first
and second EF hands.
gem1 cells display phenotypes related to ERMES
deficiencies. As noted above, Gem1 co-segregated with other
ERMES proteins in an unbiased genetic interaction map,
indicating that gem1 and ERMES-deficient cells suffer from
a common problem [14].
Among the analysed genetic interactions are a series of
synthetic phenotypes of enzymes of the CL (cardiolipin) (diphosphatidylglycerol) biosynthesis pathway. Like ERMES
core components, Gem1 is synthetically lethal with enzymes
of the CL biosynthesis pathway [26,29], consistent with a role
for Gem1 in regulating ERMES action on lipid metabolism.
Accordingly, expressing a mutant form of Gem1 incapable
of localizing to ERMES does not cure this synthetic lethality.
Interestingly, although correctly localized to ERMES,
mutants of the second GTPase domain are incapable of
rescuing the synthetic lethality [26,30].
This suggests a model in which both GTPase domains
perform distinct functions. The first domain localizes Gem1
to ERMES, and, once localized, Gem1 acts in the lipid
biosynthesis pathway via its second GTPase domain. The
cues to which Gem1 responds as well as Gem1’s action on
ERMES remain to be identified.
Miro GTPases have conserved roles at the
ER–mitochondria interface
Gem1 stands out among the ERMES components, because
it is highly conserved [28]. Miro GTPases are found in most
eukaryotes, with members in distant phyla such as metazoans,
fungi [31], plants [32] and many protists. This contrasts with
Cellular Traffic of Lipids and Calcium at Membrane Contact Sites
the remaining components of the ERMES complex, which
can be unambiguously identified only in fungi [17].
Mammals actually have two isoforms of Miro, Miro-1
and Miro-2, that are both important for Ca2 + -regulated
mitochondrial movement along microtubules [33,34]. Using
a monoclonal antibody against Miro-1 we showed that Miro1 is found in few foci on the mitochondrial surface, which are
highly reminiscent of ERMES foci. Moreover, those foci are
systematically found at sites where the ER and mitochondria
overlap, suggesting that Miro-1 is preferentially found at ER–
mitochondria connections, probably embedded in a tethering
complex [26].
Outlook
The molecular mechanisms that mediate ER–mitochondria
communication are still poorly understood. Recent years
have seen major advances, and common themes in
organelle tethering are emerging. The search for an ER–
mitochondria tethering complex was originally motivated by
the supposed central role of the ER–mitochondria connection
in lipid and Ca2 + exchange between the two organelles. The
discovery of ERMES now extends the physiological scope
of ER–mitochondria connection to additional functions such
as mtDNA replication and mitochondrial protein import.
Although the connection between those processes is unclear,
their remarkable diversity suggests that ER–mitochondria
contact sites represent a major site of communication
between mitochondria and the rest of the cell [25,26]. Future
research will probably provide an integrated view of these
communication routes. Important questions include how
lipids are extracted from some membranes and delivered to
others; how are ERMES complexes physically connected
to the mitochondrial genome in a large assembly spanning
the ER, the OMM and the IMM; last, but not least, what
is the molecular nature of the tethering complex(es), if any, to
which Miro proteins are associated in metazoan cells.
Funding
The BK laboratory is supported by the Swiss National Science
Foundation [grant number PPOOP3-133651].
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Received 1 November 2011
doi:10.1042/BST20110758