Integrative functions of the mitochondrial contact site and cristae organizing system

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Review

Integrative functions of the mitochondrial contact site and cristae organizing system Stefan Schorr, Martin van der Laan ∗ Medical Biochemistry and Molecular Biology, Center for Molecular Signaling, PZMS, Saarland University, School of Medicine, 66421, Homburg, Germany

a r t i c l e

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Article history: Received 26 July 2017 Received in revised form 13 September 2017 Accepted 14 September 2017 Available online xxx Keywords: MICOS Cristae Mitochondria Protein sorting Membrane architecture Contact sites

a b s t r a c t Mitochondria are complex double-membrane-bound organelles of eukaryotic cells that function as energy-converting powerhouses, metabolic factories and signaling centers. The outer membrane controls the exchange of material and information with other cellular compartments. The inner membrane provides an extended, highly folded surface for selective transport and energy-coupling reactions. It can be divided into an inner boundary membrane and tubular or lamellar cristae membranes that accommodate the oxidative phosphorylation units. Outer membrane, inner boundary membrane and cristae come together at crista junctions, where the mitochondrial contact site and cristae organizing system (MICOS) acts as a membrane-shaping and −connecting scaffold. This peculiar architecture is of pivotal importance for multiple mitochondrial functions. Many elaborate studies in the past years have shed light on the subunit composition and organization of MICOS. In this review article, we summarize these insights and then move on to discuss exciting recent discoveries on the integrative functions of MICOS. Multifaceted connections to other major players of mitochondrial biogenesis and physiology, like the protein import machineries, the oxidative phosphorylation system, carrier proteins and phospholipid biosynthesis enzymes, are currently emerging. Therefore, we propose that MICOS acts as a central hub in mitochondrial membrane architecture and functionality. © 2017 Elsevier Ltd. All rights reserved.

Contents 1. 2. 3. 4. 5. 6. 7.

Introduction: Endless forms most beautiful . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Formation and maintenance of mitochondrial cristae membranes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Mitochondrial contact site and cristae organizing system (MICOS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Role of MICOS in mitochondrial protein biogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Cristae architecture, energy metabolism and calcium handling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Connections between MICOS and phospholipid metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Outlook: MICOS as a central hub in mitochondrial physiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

Abbreviations: CL, cardiolipin; ERMES, ER-mitochondria encounter structure; ERMIONE, ER-mitochondria organizing network; MCU, mitochondrial calcium uniporter; MIA, mitochondrial intermembrane space import and assembly; MICOS, mitochondrial contact site and cristae organizing system; MicX, Mic protein of X kDa (subunit of MICOS); OPA1, optic atrophy 1; PA, phosphatidic acid; PC, phosphatidylcholine; PE, phosphatidylethanolamine; PS, phosphatidylserine; SAM, sorting and assembly machinery; TIM23, presequence translocase of the inner mitochondrial membrane; TOM, translocase of the outer mitochondrial membrane; VDAC, voltagedependent anion channel. ∗ Corresponding author at: Medical Biochemistry and Molecular Biology, Saarland University, School of Medicine, Kirrberger Straße 100, Building 45.2, 66421 Homburg, Germany. E-mail address: [email protected] (M. van der Laan).

1. Introduction: Endless forms most beautiful Eukaryotic cells contain a fascinating variety of structurally and functionally distinct intracellular membrane systems, termed organelles. This intricate inner organization allows to delineate specialized subcompartments dedicated to distinct biochemical processes, which would often be conflicting within the same compartment. In this way, the functional repertoire of eukaryotic cells is tremendously expanded compared to prokaryotes. Concentration gradients of ions and other compounds may be explored for energy conversion or signal transmission. Anabolic and catabolic pathways

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may be segregated and coordinated to achieve an unprecedented metabolic plasticity. However, compartmentalization also comes with a burden: the coordination of cellular functions now requires the transport of macromolecules, like proteins, metabolites and information between organelles across one or more selectively permeable membranes. Earlier research in organelle biology has focused on the assignment of discrete biochemical and physiological functions and the mechanisms of transport into and out of membrane-bound compartments. More recently, substantial efforts have been made to better understand the interaction and communication of organelles and the functional implications of the intriguing organellar membrane architecture [1–5]. A prime example of this development is the ongoing advancement in our understanding of the structural and functional organization of mitochondria [6–11]. These large organelles of endosymbiotic origin form extensive and highly ramified tubular networks that in most cell types propagate throughout the entire cytosol [12]. They contain a small circular genome that is organized into nucleoids and encodes for a few mitochondrial proteins as well as ribosomal and transfer RNAs [13,14]. The ultrastructure of mitochondria is particularly complex, because they are made up of two membrane systems that are termed outer and inner mitochondrial membrane, respectively. The outer mitochondrial membrane is much more than just a simple physical perimeter with large metabolite-conducting pores. Instead it assures the selective targeting and entry of more than thousand different proteins encoded by nuclear genes into mitochondria [15–20]. The outer membrane constitutes a versatile signaling platform and guides the communication of mitochondria with other organelles, like the endoplasmic reticulum [21]. The signal-dependent permeabilization of the outer mitochondrial membrane sends cells to their apoptotic doom [22,23]. The inner membrane is composed of two morphologically distinguishable domains with particular, yet tightly linked, functions in mitochondrial physiology [24–26]. The inner boundary membrane is enriched in transport machineries for metabolites and proteins. It mostly huddles against the outer membrane confining the narrow intermembrane space. Particularly protein-dense, tubular or lamellar membrane structures sprout from the inner boundary membrane into the central matrix compartment that may occupy a substantial part of the mitochondrial volume in heavily respiring cells [9,24–30]. These cristae membranes contain the oxidative phosphorylation machinery that produces ATP, the universal cellular energy currency, from ADP and phosphate via a sophisticated chemi-osmotic coupling of the proton-pumping respiratory chain complexes to the proton-gradient-consuming F1 Fo -ATP synthase. The ultrastructure of the narrow cristae tubules and discs appears to be perfectly tweaked for this process (24,25). Thus, cristae membranes are the actual biochemical reactors within mitochondria, the power plants of eukaryotic cells.

2. Formation and maintenance of mitochondrial cristae membranes Different views on the mechanisms of mitochondrial cristae formation have been discussed (summarized in: [26]). In the unicellular eukaryotic model organism baker’s yeast (Saccharomyces cerevisae), mitochondria contain only few, small cristae, when cells are grown in the presence of the fermentable carbon source glucose. Under these conditions, yeast cells produce ATP mainly via glycolysis in the cytosol. When cells are then transferred into a medium only containing non-fermentable carbon sources, like glycerol or lactate, expression of a plethora of (glucose-repressed) genes is induced. Nuclear and mitochondrial encoded components of the oxidative phosphorylation machinery are synthesized and inserted into the mitochondrial inner membrane. The surface of

the inner membrane expands and because the outer membrane does not grow to the same extent, invaginations of the inner membrane towards to matrix appear inevitable [31]. Moreover, membrane protein crowding supports membrane bending [32]. It is well established that dimers and oligomers of the F1 Fo -ATP synthase are crucial factors for shaping the inner mitochondrial membrane [33–38]. ATP synthase dimers have an angular shape imposing curvature on the resident membrane. Long rows of ATP synthase dimers line up at the tips and rims of cristae membranes and are required for their formation and/or stability. Thus, initially shallow invaginations of the inner mitochondrial membrane may be stabilized and shaped into cristae-like structures by the accumulation of ATP synthase dimers and oligomers. Respiratory chain (super-)complexes and other cristae-resident proteins likely contribute to this process. The outgrowth of cristae membrane domains consequently generates a strong membrane curvature at the origin, where the cristae remain connected to the inner boundary membrane. In electron micrographs, these neck regions present as regularly shaped narrow tubular membrane domains that have been termed crista junctions [24–26]. The formation of crista junctions is critical for the ultrastructure and functionality of mitochondria. These structures not only stabilize the strong membrane curvature at the base of the cristae, but also act as diffusion barriers for proteins and likely also metabolites [39]. They are crucial for the asymmetric protein distribution between inner boundary and cristae membranes [26]. The molecular nature of crista junctions and their protein composition was long enigmatic. Early studies had implicated the conserved dynamin-like GTPase OPA1 (Mgm1 in yeast) in the regulation of crista junctions and, hence, the mobilization of cytochrome c from intracristal pools at the onset of apoptosis [40–43]. However, a strict requirement for OPA1/Mgm1 for the formation of crista junctions has been refuted recently [44]. OPA1/Mgm1 was initially identified as an essential factor for inner membrane fusion and several lines of evidence suggest that the contributions of OPA1 in higher eukaryotes and Mgm1 in yeast to cristae architecture and remodeling may differ [3,45]. A recent seminal paper by Walter Neupert and colleagues [46] has put forward an appealing and very elegant model for the interplay of mitochondrial fusion and cristae formation. They propose that two pathways of cristae formation exist. Tubular cristae are formed by membrane outgrowth and ATP synthase-dependent membrane shaping as described above. Alternatively, lamellar cristae may be formed by an incomplete inner membrane fusion event. The authors argue that Mgm1 fusion activity in yeast depends on its interaction with the outer membrane fusion complex Fzo1/Ugo1 [47,48]. Thus, inner membrane fusion occurs at contact sites between inner and outer mitochondrial membranes. At late stages of the fusion reaction a narrow tubular structure will remain which resembles a crista junction. Stabilization of this structure will lead to the formation of a disc-shaped crista domain [46]. The molecular mechanisms of such a process and the crosstalk of the protein machineries involved remain unclear. However, the model would explain several earlier observations regarding the mutual relationship between mitochondrial dynamics and cristae biogenesis. Follow-up studies based on this intriguing hypothesis will certainly lead to novel insights into mitochondrial architecture and homeostasis.

3. Mitochondrial contact site and cristae organizing system (MICOS) Independent of the question how cristae formation is initiated, crista junction structures obviously need to be stabilized by a protein machinery given their regular shape and immense membrane curvature. This serious gap in previous models was closed a cou-

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ple of years ago, when the evolutionary conserved mitochondrial contact site and cristae organizing system (MICOS) was identified [49–52]. This huge protein complex is composed of at least six different proteins (seven in vertebrates) that are strongly enriched at crista junctions (for a consensus nomenclature see: [53]) (Fig. 1). MICOS is made up of two subcomplexes that both contribute to membrane curvature induction and stabilization [54–57]. One subcomplex is composed of Mic60 (formerly known as mitofilin or Fcj1) and Mic19. In vertebrates a paralog of Mic19, termed Mic25, is part of this MICOS module [55,58,59]. The Mic60 protein is composed of an amino-terminal transmembrane segment and a large hydrophilic domain exposed to the intermembrane space [60]. This hydrophilic domain contains an extended coiled-coil region and a carboxy-terminal mitofilin signature domain that represents the best conserved part of the protein. The mitofilin domain contributes to homotypic interactions between Mic60 molecules and cooperates with the coiled-coil region in connecting MICOS to the outer mitochondrial membrane [61,62]. Binding partners of the Mic60containing subcomplex in the outer membrane include the general preprotein translocase of the outer mitochondrial membrane (TOM complex) and the sorting and assembly machinery (SAM complex; also known as TOB complex) for the biogenesis of ␤-barrel outer membrane proteins [49–51,61–68]. Thus, Mic60 and MICOS are intimately involved in the formation of intra-mitochondrial membrane contact sites (Figs. 1 and 2). The linker region between the coiled-coil and mitofilin domains contains two amphipathic ␣-helices that mediate membrane binding of Mic60 independent of the amino-terminal transmembrane segment [69]. The soluble intermembrane space domain of Mic60 was recently shown to deform membranes in vitro and in vivo [69,70]. This membrane-shaping capacity is conferred by the amphipathic ␣-helical region in the linker domain, because its mutational inactivation impairs Mic60 membrane binding and remodeling [69]. Evidence has been presented that Mic19, a peripheral membrane protein exposed to the intermembrane space site of the inner membrane, regulates the membrane-shaping activity of Mic60 through binding to the carboxy-terminal mitofilin domain [69]. In vitro experiments indicate that the mitofilin domain at least partially constrains Mic60-driven membrane remodeling, which is relieved by Mic19 binding [69]. Interestingly, Mic19 contains conserved cysteine residues that form intra- and maybe also inter-molecular disulfide bonds [69,71]. It is tempting to speculate that the conserved cysteine residues of Mic19 represent a point of attack for redox-dependent regulatory processes that are involved in mitochondrial membrane remodeling, for example during stress responses [72]. Key elements of the second MICOS subcomplex are extended oligomers of the small integral membrane protein Mic10 that is considered to adopt a wedge-shaped conformation in the inner mitochondrial membrane leading to curvature induction at crista junctions [54,73]. This model of Mic10 activity is based on the in vitro reconstitution of the protein into proteoliposomes and the overexpression of Mic10 in yeast cells. Reconstituted oligomeric Mic10 deforms liposomes and induces the formation of cristae-like invaginations [73]. Overexpression of Mic10 in vivo leads to inner membrane deformation and expansion of crista junctions [54]. Mutational analysis has revealed that highly conserved glycinerich motifs in both transmembrane segments of Mic10 drive oligomerization [54,73]. The Mic10-containing MICOS subcomplexes additionally comprehend Mic26 and Mic27, two integral inner membrane proteins that belong to the same protein family, but likely fulfill distinct functions [49–51,54–56,74,75]. In yeast, Mic27 was found to promote the formation of Mic10 oligomers [57]. The role of Mic26 is less clear, but seems to be more prominent in higher eukaryotes [75]. Because Mic26 and Mic27 possess phospholipid-binding activities, it is thought that both proteins are

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involved in the crosstalk of MICOS proteins and membrane lipids [74,75]. Although this aspect of crista junction formation remains to be investigated in detail, a close cooperation of membrane proteins and phospholipids at crista junctions appears self-evident [30,76]. Finally, the small integral membrane protein Mic12 in yeast as well as its mammalian paralog QIL1 (also termed MIC13) were found to connect both MICOS subcomplexes at crista junctions. Thus, Mic12/QIL1 is critical for the integrity of the holo-MICOS complex [55,57,77,78]. The central role of MICOS in crista junction formation becomes apparent from a large number of studies in different organisms that examined the consequences of MICOS disruption. Knockout of MICOS components in yeast (either individually, in pairs, or altogether) as well as their knockdown or knockout in animal and human cells generally lead to the same unambiguous phenotype, although the severity may differ. MICOS ablation causes the loss of crista junctions and the detachment of cristae membrane domains [49–52,55,56,59,60,64,74,75,77–83]. Mutant mitochondria exhibit a massive accumulation of lamellar membrane stacks in the matrix compartment with no apparent connections to the inner boundary membrane. In yeast, this defect of mitochondrial architecture is most obvious for the loss of Mic60 or Mic10 with virtually no crista junctions remaining [49–51]. Additionally, Mic60 and Mic10 are required for the stable accumulation of other MICOS subunits in mitochondria [49–51]. Therefore, these two membrane-shaping subunits are considered core components of MICOS. Lack of Mic12, Mic19 or Mic27 induces an intermediate phenotype with a decrease in the number of crista junctions and moderate accumulation of detached cristae membrane stacks [49–51]. Studies on individual MICOS components in mammalian cells are complicated by the fact that the mutual interdependencies of the subunits with respect to protein stability are more pronounced and, therefore, the severity of mutant phenotypes is less differentiated [55,59,64,74,75,77,79,82,83]. A particularly interesting case is Mic26, because loss of this protein leads to deleterious effects on mitochondrial architecture and functionality in mammalian cells [75], but has no discernible consequences in yeast [49–51]. This may reflect functional divergence during evolution. However, it should be noted that the precise evolutionary relationships between yeast and mammalian Mic26 and Mic27 are still under debate [84,85]. In summary, MICOS is required for the formation and/or stability of crista junctions independent of the respective pathway of cristae biogenesis. One may interpret the majority of the available data on MICOS function as argument for a late role in cristae formation. On the other hand, there is also evidence that MICOS proteins may define at an early stage the sites were cristae membranes are formed [56]. Moreover, the fact that both Mic60 and Mic10 possess an intrinsic membrane-curvature-inducing activity suggests that MICOS (or its subcomplexes) may have a more active role during cristae biogenesis. This function may go clearly beyond the plain stabilization of the neck region of cristae when membrane tension becomes critical to prevent cristae membranes from pinching off the inner boundary membrane. Clearly, more work is required to clarify the direct roles of MICOS subunits in the generation and maintenance of mitochondrial membrane architecture and heterogeneity.

4. Role of MICOS in mitochondrial protein biogenesis It is well established by now that MICOS is an intricate molecular machine critical for mitochondrial membrane architecture. But the functions of MICOS, its subcomplexes and individual protein components clearly extend beyond the stabilization of crista junctions. For example, the MICOS core component Mic60 was

Please cite this article in press as: S. Schorr, M. van der Laan, Integrative functions of the mitochondrial contact site and cristae organizing system, Semin Cell Dev Biol (2017), http://dx.doi.org/10.1016/j.semcdb.2017.09.021

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Fig. 1. The mitochondrial contact site and cristae organizing system (MICOS) promotes protein import and sorting via the mitochondrial intermembrane space assembly (MIA) pathway and the sorting and assembly machinery (SAM) for ␤-barrel protein import and folding in the outer membrane. Import sites for presequence-carrying preproteins formed by the general preprotein translocase of the outer membrane (TOM complex) and the presequence translocase of the inner membrane (TIM23 complex) accumulate in the vicinity of MICOS at crista junctions. OM, outer mitochondrial membrane; IM, inner mitochondrial membrane; IMS, intermembrane space; 10, Mic10; 12, Mic12 (QIL1); 25, Mic25; 26, Mic26; 27; Mic27; 60, Mic60; CC, coiled-coil region of Mic60; MF, carboxy-terminal mitofilin domain of Mic60; OPA1, optic atrophy 1 (Mgm1 in yeast); PAM, presequence translocase-associated import motor.

shown to promote protein import and assembly into the intermembrane space and outer membrane compartments of mitochondria (Fig. 1) [51,66,86]. The mitochondrial intermembrane space assembly (MIA) pathway mediates the import and oxidative folding of cysteine-rich client preproteins of the intermembrane space (reviewed in: [87–89]). These preproteins initially enter mitochondria via the TOM complex in the outer membrane and subsequently engage with their receptor Mia40 in the intermembrane space. Substrate interaction of Mia40 occurs via a hydrophobic binding cleft on the surface of the protein [90,91]. At an early stage of the import reaction transient intermolecular disulfide bonds are formed between Mia40 and the incoming preprotein. The disulfide is transferred to the preprotein resulting in its oxidative folding and trapping in the intermembrane space. Redox-active cysteine residues in Mia40 itself become reduced in this process and are re-oxidized by the sulfhydryl oxidase Erv1 (Fig. 1) [92–94]. Mic60 transiently interacts with Mia40 and promotes preprotein import by recruiting Mia40 to the intermembrane space side of the TOM complex. This spatial coupling function of Mic60 facilitates the formation of intermolecular disulfide bonds between Mia40 and the preprotein in close proximity to the TOM complex preventing the exposure of potentially redox-sensitive cysteine residues in the preproteins (Fig. 1) [51]. However, recent studies indicate that Mia40 can also associate with cysteine-free preprotein variants indicating that hydrophobic interactions are in principle sufficient for substrate trapping [95,96]. It will be interesting to learn if Mic60 also supports the import of such non-canonical Mia40 substrates into mitochondria. The multi-step biogenesis of outer membrane ␤-barrel proteins requires a close cooperation of the TOM complex and the SAM complex (Fig. 1) (reviewed in: [20]). After passage through the TOM complex, ␤-barrel preproteins are inserted into the outer membrane and folded by SAM. This process involves the formation of TOM-SAM supercomplexes for preprotein handover [97,98]. Mic60-deficient mitochondria are impaired in ␤-barrel protein biogenesis [66]. Mic60 interacts with both SAM and TOM, but a first study suggested that its role is related to the initial TOM-dependent import of ␤-barrel precursors into the intermembrane space [66].

It is currently unclear, how Mic60 supports ␤-barrel biogenesis. It seems possible that Mic60 not only affects early stages of ␤-barrel preprotein import, but may also support TOM-SAM supercomplex formation and, hence, preprotein transfer. Certainly, further studies are needed to clarify this issue. The majority of nuclear-encoded mitochondrial preproteins carry amino-terminal, cleavable signal sequences that guide them to the inner membrane or matrix (reviewed in: [17,99,100]). A key step in this import pathway is the handover of preproteins from the TOM complex to the presequence translocase of the inner mitochondrial membrane (TIM23 complex) and the formation of two-membrane-spanning translocation intermediates (Fig. 1). A physical interaction between MICOS and TIM23 complexes has not been described so far. TIM23-dependent preprotein import requires the membrane potential across the inner mitochondrial membrane which is reduced in MICOS-deficient mitochondria [51]. The observed moderate inhibition of presequence protein import into mitochondria lacking Mic60 is therefore likely an indirect effect [51]. However, a recent study on the distribution of presequence protein import sites across the mitochondrial surface revealed a clustering of translocation-arrested TOM-TIM23 supercomplexes in the vicinity of crista junctions [101]. The molecular basis of this non-random localization of import sites in not known. Proximity of presequence protein import sites and crista junctions may facilitate the intra-mitochondrial sorting of the highly abundant respiratory chain complex components to pre-existing or expanding cristae membrane domains. This view is supported by the notion that MICOS-containing membrane contact sites can be enriched by the expression of a GFP-Tim23 fusion protein that tethers inner and outer mitochondrial membranes [49]. 5. Cristae architecture, energy metabolism and calcium handling If one assumes that mitochondrial cristae membranes provide a highly specialized sub-compartment perfectly adapted to support oxidative phosphorylation, bioenergetic defects in mitochondria with perturbed inner membrane architecture are to be expected.

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Fig. 2. Hypothetical connections of MICOS-dependent mitochondrial membrane architecture to calcium (left) and phospholipid (right) homeostasis. ER, endoplasmic reticulum; OM, outer mitochondrial membrane; IM, inner mitochondrial membrane, IMS, intermembrane space; IP3 R, inositol-3-phosphate receptor; RyR, ryanodine receptor; GRP75, glucose-regulated protein 75; VDAC, voltage-dependent anion channel (porin); MFN1/2, mitofusin 1 and 2, respectively; MCU, mitochondrial calcium uniporter; MICU1/2, mitochondrial calcium uptake proteins 1 and 2, respectively; 10, Mic10; 12, Mic12; 25, Mic25; 26, Mic26; 27; Mic27; 60, Mic60; CC, coiled-coil region of Mic60; MF, carboxy-terminal mitofilin domain of Mic60; OPA1, optic atrophy 1 (Mgm1 in yeast); ERMES, ER-mitochondria encounter structure; SAM, sorting and assembly machinery; mtDNA, mitochondrial DNA; TCA, tricarboxylic acid.

Indeed, yeast cells lacking Mic60 or Mic10 show reduced growth on non-fermentable media where high mitochondrial activity is required [49–51,102]. Isolated Mic60- or Mic10-deficient mitochondria exhibit a decreased inner membrane potential, reduced oxygen consumption under conditions of basic, coupled and maximal respiration and lower activities of individual respiratory chain complexes [51,54]. Impaired respiration upon ablation of MICOS subunits was likewise found in mammalian cells [55,59,74,75,77]. In agreement with these observations, loss of OPA1 which also remodels cristae membranes in mammalian cells was reported to induce perturbations of respiratory chain organization and activity [103]. Although the idea that mitochondrial membrane architecture per se is required for optimal oxidative phosphorylation is intuitively correct, the underlying molecular mechanisms may be more wide-ranging. What happens if mitochondrial cristae are detached from the inner boundary membrane, where preprotein import via the TOM and TIM23 machineries necessarily takes place [17,99,100]? Many of the newly incoming presequence-carrying preproteins are subunits of respiratory chain complexes that should be largely entrapped in the detached cristae membranes of MICOSdeficient mitochondria. Additionally, it is tempting to speculate that respiratory chain maintenance and turnover by the mitochondrial protein quality control system [104] may be similarly hindered. Increased generation of reactive oxygen species by damaged respiratory chain complexes can be considered as possible consequence. Moreover, oxidative phosphorylation involves the export of ATP from the mitochondrial matrix via ADP/ATP carriers, a process required to drive energy-consuming processes in other cel-

lular compartments [105]. ADP/ATP carriers that are likely present in the detached cristae membranes of MICOS-deficient mitochondria could at best transport ATP into enclosed, intra-mitochondrial vesicular compartments. Moreover, ADP from the cytosol will not be able to reach the entrapped ADP/ATP carriers to function as counter-substrate. Stringent calcium homeostasis is critical for cellular survival [106,107]. Cytosolic calcium concentrations are kept very low, whereas the endoplasmic reticulum (ER) serves as the major calcium storage compartment (Fig. 2). Release of calcium from the ER upon an adequate signal, for example via the inositol3-phosphate (IP3 ) or ryanodine receptors, triggers a plethora of cellular responses and signaling cascades [106,107]. These calcium signals are limited in space and time by the activity of the sarco-endoplasmic reticulum calcium ATPase (SERCA) that pumps calcium ions back into the ER. Additionally, mitochondria act as calcium buffer compartments and take up calcium released from the ER at contact sites between both organelles (Fig. 2) [107–109]. The molecular nature of these contact sites is still highly controversial, but several lines of evidence point to a key role of mitofusin 2 (MFN2) in mammalian cells [110–112]. MFN2 exhibits a dual localization in the mitochondrial outer membrane and the ER membrane and is thought to tether these membranes via homotypic in trans interactions (Fig. 2). Heterotypic tether complexes formed by MFN2 in the ER and mitofusin 1 (MFN1) in the mitochondrial outer membrane have been found, too [110]. Calcium enters the mitochondrial matrix via the VDAC (porin) complexes in the outer membrane and the mitochondrial calcium uniporter (MCU)

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Fig. 3. The mitochondrial contact site and cristae organizing system (MICOS) as a central hub of membrane architecture and organelle function. Left: Network of mitochondrial protein machineries centered around MICOS. Right: Functional modules of mitochondrial biology connected to MICOS. Solid lines indicate a direct link to MICOS, whereas dashed lines refer to hypothetical long-range connections via MICOS. OM, outer mitochondrial membrane; IM, inner mitochondrial membrane, IMS, intermembrane space; VDAC, voltage-dependent anion channel (porin); SAM, sorting and assembly machinery; TOM, translocase of outer mitochondrial membrane; OPA1, optic atrophy 1; TIM23, presequence translocase of the inner mitochondrial membrane; mtDNA, mitochondrial DNA; Resp. Chain, Respiratory chain complexes, F1 Fo , F1 Fo -ATP synthase.

in the inner membrane [107–109,113]. A direct linkage between IP3 receptors and VDAC channels via glucose-regulated protein 75 (GRP75) has been proposed [114]. Independent of the exact molecular nature of the ER-mitochondria tether, it seems clear that close apposition of the three membranes separating the ER lumen from the mitochondrial matrix is necessary for efficient calcium transmission, because the calcium affinity of MCU is surprisingly low [107–109,113]. Therefore, close proximity of ligand-gated calcium release channels of the ER, VDAC complexes, and MCU complexes is thought to be critical, so that a spatially restricted micro-domain of high calcium concentration is formed (Fig. 2) [107–109]. It has been demonstrated that an impairment of ER-mitochondria tethering indeed leads to decreased inter-organellar calcium transmission [110,111]. But how is VDAC linked to MCU? A direct interaction between both channels has not been demonstrated yet, but contact sites between inner and outer mitochondrial membranes are likely involved [115]. MICOS considerably contributes to intra-mitochondrial membrane contact site formation in all organisms examined. Because mitochondrial matrix calcium supports ATP synthesis (mainly via activation of tricarboxylic acid cycle enzymes [108,109,113]), impaired mitochondrial calcium uptake may contribute to the bioenergetic defects of MICOS-deficient cells under appropriate conditions (Fig. 2). This may not only be due to impaired contact site formation. A fraction of MCU molecules may localize to detached cristae membranes in MICOS-deficient mitochondria and would therefore be completely separated from VDAC-mediated calcium influx. Intriguingly, an elegant recent study demonstrated that in mammalian cells Mia40 (also termed CHCHD4) mediates the formation of a functionally important disulfide linkage between MICU1 and MICU2, both of which are regulatory subunits of the MCU complex [116]. Although it has not yet been formally shown that mammalian CHCHD4 associates with MICOS like yeast Mia40, it is tempting to speculate that such a crosstalk exists and may link MICOS to the assembly and regulation of MCU complexes (Figs. 2 and 3 and ). Certainly, further experiments are necessary to clarify this exciting hypothesis.

6. Connections between MICOS and phospholipid metabolism In many cases membrane contact sites in cells are involved in phospholipid transport between different compartments. Most phospholipid biosynthesis pathways are mainly localized to the ER membrane, but several important steps occur at other intracellular compartments [117]. Mitochondria contribute to cellular phos-

pholipid production for example by synthesizing cardiolipin (CL) starting with phosphatidic acid (PA) precursors mainly imported from the ER [118,119]. Phosphatidylserine (PS) is converted to phosphatidylethanolamine (PE) by the mitochondrial PS decarboxylase Psd1 [117–119]. Synthesis of phosphatidylcholine (PC) from PE again takes place in the ER membrane [117–119]. Studies in yeast have indicated that shuttling of phospholipids between mitochondria and ER is likely mediated by the ER-mitochondria encounter structure (ERMES) (Fig. 2) [120–122]. ERMES is composed of the mitochondrial outer membrane proteins Mdm10 and Mdm34, the cytosolic adaptor protein Mdm12 and the ERresident integral membrane protein Mmm1 [120]. The conserved calcium-activated GTPase Gem1 (Miro1 and Miro2 in mammals) associates with ERMES and has been suggested to promote the clustering of tether complexes [123,124]. Clear mammalian homologues of the ERMES core components have not been identified thus far. However, so called synaptotagmin-like, mitochondrial and lipid-binding protein (SMP) domains that contain a phospholipidbinding cavity are present in Mdm34, Mdm12, and Mmm1 [121,125]. Intriguingly, Mdm10 is not only found in ERMES complexes, but also associates with SAM complexes to mediate an early step of TOM complex assembly [126–128]. As described above SAM physically associates with MICOS. Furthermore, ERMES and MICOS are connected via genetic interactions [50]. Thus, an ER-mitochondria organizing network (ERMIONE) is emerging that links mitochondrial membrane architecture and organelle contact sites to the biogenesis and transport of phospholipids and proteins [129]. First insights into phospholipid transfer between outer and inner mitochondrial membranes came from work on the conserved intermembrane space proteins Ups1 and Ups2 [130–133]. They both associate with the same partner protein, termed Mdm35, to form intermembrane space shuttling complexes for PA (Ups1/Mdm35) or PS (Ups2/Mdm35) (Fig. 2). In the inner membrane, PS is then converted to PE by Psd1. However, Ups2/Mdm35-dependent shuttling of PS is not essential for PE synthesis in mitochondria. A recent study demonstrated that inner membrane-localized Psd1 can decarboxylate PS also in trans in the outer membrane [134]. The in trans activity of Psd1 requires MICOS-mediated contact sites between inner and outer mitochondrial membranes [134] (Fig. 2). This striking finding will certainly prompt further studies on the role of MICOS in the organization and regulation of phospholipid metabolism. Initial observations give rise to great expectations: For example, MICOS has been linked to CL remodeling mediated by the transacylase tafazzin (Taz1) in yeast [102]. Studies on lipid trafficking in plant mitochondria point to a

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critical role for Mic60 in the export of PE and the import of galactophospholipids from plastids under starvation conditions [68].

Therefore, we dare to conclude with the prediction: The era of MICOS and ERMIONE has only just begun!

7. Outlook: MICOS as a central hub in mitochondrial physiology

Acknowledgements

Taken together, the mitochondrial contact site and cristae organizing system is a critical determinant of mitochondrial membrane architecture and physiology. Its intimate crosstalk with many other protein machineries of mitochondria identifies MICOS as a central hub in an intertwined network that assures mitochondrial functionality and integration into the cellular context (Fig. 3). This network extends across three intracellular membranes and links mitochondria and the ER. Our understanding of the integrative functions of MICOS is still at the very beginning and many novel factors and connections remain to be discovered. For example, the molecular reasons for the massive disorganization and aggregation of mitochondrial nucleoids in MICOS-deficient cells are completely unclear [83,135]. Of note, mitochondrial DNA synthesis appears to be linked to ER-mitochondria contact sites in human cells [136]. Mitochondrial inner membrane nano-architecture and heterogeneity is a subject of intense investigation. Recent studies have shed first light on the interaction and functional cooperation between MICOS and OPA1 in the formation and regulation of crista junctions in mammalian cells, however the underlying molecular mechanisms are not understood [44,137]. The membrane-shaping activities of ATP synthase and MICOS may be dynamically adjusted to modulate cristae shape. Interestingly, a fraction of the MICOS core subunit Mic10 was found to associate with dimeric ATP synthase complexes likely via the dimer-specific subunit Su e (Atp21/Tim11) [138]. This interaction was found to promote the formation of ATP synthase oligomers. It will also be exciting to learn more about, if and how MICOS (sub-)complexes contribute to the remodeling of mitochondrial ultrastructure during metabolic adaptation and stress responses. Another central challenge is to obtain further insights into the physiological roles of MICOS-mediated contact sites between inner and outer mitochondrial membranes. The groundbreaking findings described in this article and many additional pieces of circumstantial evidence suggest that intra-mitochondrial membrane contact sites act as metabolic and signaling hotspots (Fig. 3). A remarkable number of further MICOS-interacting proteins, especially in mammalian cells, has been reported suggesting that several mitochondrial and cellular functions and pathways merge at crista junctions. Among these proteins are Disrupted-in-schizophrenia 1 (DISC1), DNAJC11, CHCHD10, and TMEM11 (recently reviewed in: [10,30,139,140]). Future studies on these proteins will not only tell us more about the regulation of MICOS, but also provide a better understanding of the mutual connections between cristae homeostasis and the communication of mitochondria with the ER. An exciting new player in this game may be the mitochondrial outer membrane protein SLC25A46 that was recently found associated with several key components of ERMIONE including MICOS. SLC25A46 deficiency appears to impact on many mitochondrial functions − either directly or indirectly − and mutations in the corresponding gene are associated with a large spectrum of human diseases [141–145]. Likewise, genuine MICOS subunits and several other MICOS-interacting proteins have been linked to diverse pathologies, like diabetic cardiomyopathy, hepatoencephalopathy, amyotrophic lateral sclerosis, frontotemporal dementia, and complex motor neuron disorders [recently reviewed in: [10,30,139,140]), These intriguing connections have further increased the general interest in deciphering the construction and organization principles of the protein networks at crista junctions.

We would like to thank Florian Wollweber and Dr. Karina von der Malsburg for stimulating discussions. Work in the authors’ laboratory is supported by the Deutsche Forschungsgemeinschaft, Sonderforschungsbereich 894 and International Research Training Group 1830.

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Please cite this article in press as: S. Schorr, M. van der Laan, Integrative functions of the mitochondrial contact site and cristae organizing system, Semin Cell Dev Biol (2017), http://dx.doi.org/10.1016/j.semcdb.2017.09.021