Chemistry and Physics of Lipids 179 (2014) 32–41

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Mitochondrial cardiolipin/phospholipid trafficking: The role of membrane contact site complexes and lipid transfer proteins Uwe Schlattner a,b,∗ , Malgorzata Tokarska-Schlattner a,b , Denis Rousseau a,b , Mathieu Boissan c,d,e , Carmen Mannella f , Richard Epand g , Marie-Lise Lacombe c,d a

Univ. Grenoble-Alpes, Laboratory of Fundamental and Applied Bioenergetics (LBFA) and SFR Environmental and Systems Biology (BEeSy), Grenoble, France Inserm, U1055, Grenoble, France c UPMC Université Paris 06, Paris, France d Inserm, UMRS938, Paris, France e Hôpital Tenon, AP-HP, Service de Biochimie et Hormonologie, Paris, France f Wadsworth Center, New York State Department of Health, Albany, NY, USA g Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada b

a r t i c l e

i n f o

Article history: Available online 26 December 2013 Keywords: Cardiolipin Creatine kinase Endoplasmic reticulum Lipid trafficking Lipid transfer proteins Lipid Transport Membrane contact sites Membrane junction complexes Mitochondria Nm23 Nucleoside diphosphate kinase.

a b s t r a c t Historically, cellular trafficking of lipids has received much less attention than protein trafficking, mostly because its biological importance was underestimated, involved sorting and translocation mechanisms were not known, and analytical tools were limiting. This has changed during the last decade, and we discuss here some progress made in respect to mitochondria and the trafficking of phospholipids, in particular cardiolipin. Different membrane contact site or junction complexes and putative lipid transfer proteins for intra- and intermembrane lipid translocation have been described, involving mitochondrial inner and outer membrane, and the adjacent membranes of the endoplasmic reticulum. An image emerges how cardiolipin precursors, remodeling intermediates, mature cardiolipin and its oxidation products could migrate between membranes, and how this trafficking is involved in cardiolipin biosynthesis and cell signaling events. Particular emphasis in this review is given to mitochondrial nucleoside diphosphate kinase D and mitochondrial creatine kinases, which emerge to have roles in both, membrane junction formation and lipid transfer. © 2014 Elsevier Ireland Ltd. All rights reserved.

1. Phospholipid/cardiolipin trafficking in mitochondria Lipids are important for mitochondrial morphology and function, including bioenergetics, biosynthetic activities, and cell signaling (reviewed in Claypool and Koehler, 2011; Nunnari and Suomalainen, 2012; Schug et al., 2012; and this issue of CPL). However, while synthesis and trafficking of mitochondrial proteins has been described in much detail during the last two decades, much less is known in this respect about mitochondrial lipids. This is certainly due to the methodological difficulties of isolating and analyzing lipids, or labeling and manipulating their levels in vivo. Nevertheless, there has been recent progress in understanding some aspects of synthesis and trafficking of mitochondrial lipids, related in particular to three aspects:

∗ Corresponding author at: Univ. Grenoble Alpes, Laboratory of Fundamental and Applied Bioenergetics (LBFA) and SFR Environmental and Systems Biology (BEeSy), Grenoble, France. Tel.: +33 476 51 46 71; fax: +33 476 51 42 18. E-mail address: [email protected] (U. Schlattner). 0009-3084/$ – see front matter © 2014 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.chemphyslip.2013.12.008

(i) Some phospholipids are synthesized within mitochondria. While the major part of cellular lipid biosynthesis takes place in the ER, mitochondria also participate. For the mitochondrial synthesis of the non-bilayer phospholipids cardiolipin (CL; Fig. 1) and phosphatidylethanolamine (PE), all involved enzymes and mostly also their localizations are known now (reviewed in Claypool and Koehler, 2011; Horvath and Daum, 2013; Osman et al., 2011). Their precursors, phosphatidic acid (PA) and phosphatidylserine (PS), respectively, have to be imported from the ER, while the products CL and PE can again be exported to the mitochondrial surface and even the ER. (ii) Mitochondrial lipids are heterogeneously distributed. Such heterogeneity exists between the mitochondrial inner (MIM) and outer membranes (MOM), but also between leaflets of a single membrane, thus creating strong asymmetries. This concerns in particular CL, which is highly enriched in MIM, in contrast to MOM and other cellular membranes that are virtually devoid of this phospholipid. Even more, the inner MIM leaflet, where CL biosynthesis proceeds, is thought to have a higher CL content as compared to the outer MIM leaflet. Breakdown

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Fig. 1. Lipid trafficking linked to cardiolipin biosynthesis, signaling and remodeling. Biosynthesis of cardiolipin (CL), the roles of CL in signaling, and the CL remodeling process involve transfer of CL or intermediates between different membranes (Claypool and Koehler, 2011; Osman et al., 2011; Schlame, 2008). Biosynthesis: CL synthesis proceeds in the inner leaflet of the mitochondrial inner membrane (MIM). The CL-precursor phosphatidic acid (PA) is mainly synthesized in the ER and has to be imported from mitochondria-associated ER membranes (MAM) via the mitochondrial outer membrane (MOM) to this MIM inner leaflet by multiple inter- and intramembrane translocation steps. In mammals, some PA may be synthesized in mitochondria. The cytidinediphosphate-diacylglycerol (CDP-DAG) synthase Tam41 (translocator assembly and maintenance), the phosphatidylglycerolphosphate (PGP) synthase Pgs1 and the phosphatidylglycerophosphatase Gep4 (genetic interactors of prohibitins) then generate the intermediates CDP-DAG, PGP and phosphatidyl glycerol (PG), respectively, that will not accumulate under normal conditions. CL is produced in a final step from PG and CDP-DAG by the cardiolipin synthase Crd1. Signaling: CL and oxidized derivatives of CL traffic to the mitochondrial surface under conditions that induce mitophagy or apoptosis, respectively. This process, which includes one inter- and two intramembrane translocation steps, seems to participate in pro-mitophagic or -apoptotic signaling (Chu et al., 2013; Kagan et al., 2009; Schlattner et al., 2013). Remodeling: The nascent CL carries mostly saturated acyl chains and is symmetric (carries the same acyl chaines on its two glycerol groups). Acyl chains are exchanged in a process called CL remodeling, which is initiated by the cardiolipin-specific deacylase Cld1 that removes an acyl chain from CL, generating monolyso-CL (MLCL). This intermediate can be used in different remodeling pathways by transacylation reactions, the by far most important being catalyzed in MIM by taffazin (Taz1; probably in the outer leaflet), and less so by MLCL acyltransferase 1 (MLCLAT1; probably in the inner leaflet). However, MLCL seems to be able to traffic also to MOM and MAM, where Taz1 and acyl-CoA lysocardiolipin acyltransferase ALCAT1, respectively, also catalyze acyl transfer to MLCL. Such ALCAT1 remodeling of CL seems to occur under pathological conditions, generating “bad” CL containing C22:6 acyl chains. Except for MLCLAT1 and ALCAT1, the specific yeast enzymes are indicated.

of these asymmetries, as observed during apoptosis, emerges as a potential signaling event (Chu et al., 2013). (iii) Mitochondrial lipids can be secondarily modified. Again, CL is a good example, since modifications concern its acyl chain composition (by a process called CL remodeling; Fig. 1 (Schlame and Ren, 2009; Yang et al., 2012)) as well as oxidative modifications of unsaturated acyl chains (Korytowski et al., 2011; SamhanArias et al., 2012). These modifications may not only provide specific functions for the lipid bilayer and protein interactions or be a simple product of oxidative stress, respectively. In particular oxidative modifications may again provide specific signals (Kagan et al., 2005). Common to these properties is the need of phospholipids to travel between specific cellular membranes and also between leaflets within these membranes. This issue has much less been studied in mitochondria, in contrast to other cellular compartments. Only recently it emerged that formation of contact sites between adjacent membranes, MIM, MOM and mitochondriaassociated membranes (MAM) of the ER are a prerequisite and possibly even sufficient for intermembrane lipid transfer (reviewed in Helle et al., 2013; Kornmann, 2013; Michel and Kornmann, 2012). In addition, first proteins in the mitochondrial intermembrane space (IMS) have been identified that could play a role as specialized lipid transfer proteins (reviewed in Tatsuta et al., 2014). We will review these issues in the following, with an emphasis on the trafficking of CL within the CL life cycle, comprising biosynthesis, remodeling, and signaling functions (Fig. 1). 2. Intermembrane lipid transfer Lipid transfer involving mitochondrial membranes does not seem to occur via vesicle trafficking, although budding of vesicles at the mitochondrial surface has been observed (reviewed in Soubannier et al., 2012) and the inverse fusion of cytosolic vesicles

with MOM cannot be excluded. For effective phospholipid transfer, rather other pathways have to be considered (Fig. 2A and B). Simple diffusion between membranes is much too slow, but different factors could accelerate such non-protein assisted transfer.

Fig. 2. Potential lipid/cardiolipin transfer mechanisms in mitochondria. (A) Transmembrane transfer of monomeric lipid/CL via free diffusion is very slow (half-times in the order of days). This may be accelerated when membranes come very close, when aqueous phase solubility is increased (as e.g. when acyl chains are removed like in mono lyso-CL), or membranes fuse and/or create inverted micelles with hexagonic phases allowing lipid/CL to diffuse between MIM and MOM leaflets (Lev, 2010). (B) Lipid transfer proteins (center, orange) can greatly facilitate this process by both lipid/CL extracting/inserting and carrier activities (Lev, 2010). It is conceivable that small proteins with hydrophobic cavity, as known in other cellular compartments, shuttle lipids, e.g. between MIM and MOM. They could be freely diffusible or anchored via a flexible domain in the MIM as proposed for the PRELI family (Potting et al., 2013). Alternatively, proteins that are known to crosslink MIM-MOM or MOM-MAM could provide transfer routes as has been proposed for NDPK-D/Nm23H4 (Schlattner et al., 2013). (C) Intra-membrane lipid transfer between the two leaflets is also rather slow when occurring spontaneously. (D) This could be again accelerated by specialized enzymes like scramblase (mixing between leaflets, ATPindependent) or flippases (directed transfer, mostly ATP-dependent). Alternatively, lipid flip-flop could possibly occur as a side-process with different transmembrane proteins.

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First, lipids could leave a membrane leaflet and solubilize more easily when their hydrophilicity is increased, either by rendering the molecule more hydrophilic (Korytowski et al., 2011), or by removing acyl chains (as e.g. in case of monolyso-CL, MLCL). Second, a close apposition of membranes may facilitate a direct flipping between adjacent leaflets of two membranes, in particular at regions of positive membrane curvature (Fig. 2A). Finally, mitochondrial lipids like CL and PE are known as non-bilayer lipids; they may form hexagonic phases in form of inverted micelles between two adjacent membranes, allowing for simple diffusion of lipids between leaflets of two membranes. Still, such mechanisms are proceeding slowly and are not regulated. Considering the strong asymmetry of mitochondrial membranes, with a CL-rich MIM and an almost CLdepleted MOM, as well as CL transfer occurring specifically during mitophagy and apoptosis, mechanisms with potential for regulation have to be considered. Such mechanisms are conceivable by protein-assisted lipid transfer (Fig. 2B). A general prerequisite for lipid transfer between MIM and MOM as well as MOM and MAM is close proximity of these membranes and their fixation by protein complexes providing a tether to form so-called membrane contact sites or membrane junctions. In addition, these structures may also have intrinsic activity for lipid extraction and transport (Helle et al., 2013). Several homo- and heterooligomeric protein complexes in the IMS can provide such functions, including nucleoside diphosphate kinase (NDPK-D/Nm23-H4), mitochondrial creatine kinase (MtCK) and the MINOS/MICO/MitOS complex in interaction with several MOM proteins (for abbreviations see Fig. 3) (Schlattner et al., 2009; van der Laan et al., 2012). Protein tethers between MOM and MAM seem to be even more diverse, with the well characterized ERMES complex in yeast, and a number of other tethers identified in vertebrates (Kornmann, 2013). In addition, the presence of classical lipid transfer proteins has been postulated. These would be diffusible factors, typically with a hydrophobic pocket and a lid, able to extract lipids from a membrane leaflet and transport it trough a hydrophilic phase (Lev, 2010, 2012). Such a system has been recently described in form of the Ups/PRELI protein family in the IMS (Tatsuta et al., 2014). The next paragraphs will focus on this protein-assisted lipid transfer between MIM, MOM and MAM, and their potential role in CL transfer.

3. MIM/MOM contact-site proteins and phospholipid transfer Contacts between MIM and MOM have been known since decades (Robertson, 1960), observed by transmission electron microscopy in negatively stained samples, and more recently by electron tomography allowing 3D-analysis (Csordas et al., 2006; Mannella, 2008). During recent years, two types of protein complexes have emerged that provide the structural basis of these contacts (Fig. 3). First, a group of homooligomeric kinases located in the IMS and enriched in contact sites (Adams et al., 1989) has the capability to cross-link two opposite membranes (Schlattner et al., 2009), namely nucleoside diphosphate kinase D (NDPKD/Nm23-H4, see Section 3.1) and mitochondrial creatine kinases (sMtCK, uMtCK, see Section 3.2). Second, a large heterooligomeric complex anchored in MIM and first described to maintain cristae junctions and morphology, the MINOS/MICOS/MitOS complex (see Section 3.3), is also able to bind to MOM proteins and could be part of a larger ER-mitochondria organizing network (van der Laan et al., 2012). For both types of protein complexes, evidence exists suggesting a role in intermembrane lipid transfer. This has been shown for the kinase complexes in vitro (Epand et al., 2007a) and in case of NDPK-D/Nm23-H4 and CL more recently also in vivo (Schlattner et al., 2013). Whether the MINOS complex has active

lipid transfer activity or rather facilitates other mechanisms via the contact formation remains to be shown. 3.1. NDPK-D/Nm23-H4 NDPK-D is a member of the NDPK/Nm23 family encoded by the NME/NM23 genes (reviewed in Boissan et al., 2009), catalyzing the transfer of ␥-phosphate between nucleoside triphosphates and diphosphates. NDPK isoforms A, B, C, and D assemble into stable hexamers of six monomers presenting two rotation-symmetrical, opposite faces (Janin et al., 2000). NDPK-D is unique in this family since it is the only one to possess a specific mitochondrial targeting sequence and to be exclusively located in mitochondria (Milon et al., 1997, 2000). NDPK-D in the IMS is bound to MIM through electrostatic interactions between CL and a basic motif (R89–R90–K91) located at a surface-exposed loop in each monomer of the hexameric complex (Tokarska-Schlattner et al., 2008). Mutation of the central arginine (R90D) strongly reduces the interaction with model liposomes containing CL and other anionic phospholipids, or with mitochondrial membranes in vivo. In HeLa cells with very low endogenous NDPK-D levels, only expression of wild type NDPK-D but not of catalytically equally active R90D mutant leads to MIM-bound enzyme and stimulation of respiration by the NDPK substrate TDP (Tokarska-Schlattner et al., 2008). This indicates local ADP regeneration by NDPK-D in the IMS, driven by mitochondrial ATP supply, and functional coupling of this NDPK-D activity with oxidative phosphorylation (Fig. 4A). We have also reported recently that NDPK-D forms a complex with the GTPase OPA1 in liver mitochondria. This suggests the involvement of the kinase in local GTP supply for OPA1-dependent mitochondrial dynamics (Schlattner et al., 2013). The NDPK-D hexamer exposes three CL binding sites (one per monomer) at the two rotation-symmetrical, opposite faces. This topology of binding sites can induce intermembrane contacts between CL-containing vesicles as has been shown in vitro (Epand et al., 2007a; Tokarska-Schlattner et al., 2008). Importantly, formation of such contact sites promotes the transfer of fluorescently labeled model lipids from donor to acceptor liposomes without inducing liposome fusion (Epand et al., 2007a). Such transfer depends on the presence of CL in both liposome populations and an intact NDPK-D binding motif (the R90D mutant is ineffective), i.e. the presence of a fully membrane-bound NDPK-D (both binding faces are membrane-bound). In mitochondria, fully membranebound NDPK-D is cross-linking MIM with MOM and thus facilitates intermembrane CL-transfer (Fig. 4A). As revealed by LC-MS-based lipidomics of MIM and MOM in HeLa cells, only overexpression of wild-type NDPK-D, but not of CL-binding deficient R90D mutant, selectively increases the CL content of MOM, while distribution of other phospholipids (e.g. phosphatidylcholine) remains unchanged (Schlattner et al., 2013). Molecular dynamics studies suggested high flexibility within the CL-binding basic loop motifs and the presence of additional secondary CL binding sites along the surface of the hexameric structure. These properties may help to extract CL from its membrane environment and to promote intermembrane CL transfer. It is further conceivable that NDPK-D hexamers, existing in equilibrium of membrane bound and unbound states, can rotate in the latter state by some sort of paddling motion predicted by anisotropic network modeling as the major dynamic property of the NDPK-D hexamer. Interestingly, the fully membrane-bound state of NDPK-D is necessary for CL transfer, but at the same time it strongly inhibits NDPK activity in vitro and in the HeLa cellular model (Schlattner et al., 2013). Possibly, membrane interaction sterically interferes with substrate access to the active site pocket, since both structural elements are in close vicinity. Based on these findings, a nanoswitch

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Fig. 3. Membrane contact site and transfer proteins potentially involved in inter-membrane lipid/cardiolipin transfer. Simplified scheme showing contact site (or membrane junction) protein complexes that tether MIM-MOM or MOM-MAM (green) and have additional lipid transfer functions (red), as well as lipid transfer proteins (orange) in the IMS. MIM-MOM contact site complexes (Schlattner et al., 2009; van der Laan et al., 2012): (i) homohexameric NDPK-D/Nm23-H4 (nucleoside diphosphate kinase D/nonmetastatic protein 23 isoform H4); (ii) homooctameric MtCK (mitochondrial creatine kinase), muscle-type sMtCK and ubiquitous uMtCK isoforms; (iii) oligomeric ATAD3 (ATPase family AAA Domain-containing protein 3), also reaching MAM via unknown interactions; (iv) heterooligomeric complex MINOS (mitochondrial inner membrane organizing system)/MICOS (mitochondrial contact site complex)/MitOS (mitochondrial organizing structure) anchored in the MIM and consisting of Fcj1 (formation of cristae junctions), Mos1 (or Mio10, mitochondrial organizing structure), and further subunits (not shown), interacts with MOM proteins TOM (translocase of outer membrane), SAM (sorting and assembly machinery), VDAC (voltage-dependent anion channel), or Ugo1 (Japanese for fusion). MOM-MAM contact site complexes (Helle et al., 2013; Kornmann, 2013): (i) heterooligomeric complex ERMES (ER-mitochondria encounter structure), with Mdm12 (mitochondrial distribution and morphology) interacting simultaneously with MOM proteins Mdm10/Mdm34 and MAM protein Mmm1 (mitochondrial morphology maintenance); (ii) homodimers of Mmr1 (mitochondrial myo2p receptor-related) interacting with unknown MOM and MAM proteins; (iii) heterodimers Mfn1-Mfn2 (mitofusin 1 and 2) or homodimers Mfn2-Mfn2; (iv) Grp75 (glucose regulated protein 75) linking MOM protein VDAC with MAM protein IP3 R (inositol triphosphate receptor); (v) heterodimers of PTPIP51 (protein tyrosine phosphatase-interacting protein 51) and VAPB (VAMP (vesicle-associated membrane protein)-associated protein B); (vi) heterodimers of Fis1 (fission 1) and Bap31 (B-cell receptor-associated protein 31). IMS lipid transfer proteins: (i) Ups (unprocessed) or PRELI (protein of relevant evolutionary and lymphoid interest) protein family, stabilized in complexes with Mdm35 or TRIAP1/p53csv (TP53-regulated inhibitor of apoptosis 1/p53-inducible cell survival factor); (ii) tBid (truncated BH3 interacting domain death agonist). Note: Most depicted proteins have been identified in yeast, and the yeast name is indicated. Homologues exist in metazoa/vertebrates, except for the ERMES complex. However, NDPK-D/Nm23H4, MtCK and ATAD3 are absent in yeast and only appeared at different time points during metazoan evolution. Inserts on bottom: Regions from a cryo-electron tomogram of an intact isolated rat liver mitochondrion (MIT) embedded in vitreous ice, with several associated ER (MAM) vesicles attached. Left insert circle: One of several 10-nm particles that span the gap between the MOM and MIM to form contact sites between the two membranes. Right insert circle: A 20-nm “tether” connecting MOM to one of the ER vesicles. The tethers vary in length and are sometimes branched. Scale bar is 50 nm.

Fig. 4. NDPK-D/Nm23-H4 and MtCK have kinase and lipid transfer functions. Current models for the function of the two oligomeric kinases NDPK-D/Nm23-H4 and MtCK in the mitochondrial intermembrane space (IMS) between inner (MIM) and outer membrane (MOM). (A) Hexameric NDPK-D can switch between phosphotransfer (kinase) and lipid transfer modes, as suggested by in vitro and cell-based experiments (Epand et al., 2007a; Schlattner et al., 2013; Tokarska-Schlattner et al., 2008). Left: In phosphotransfer mode (elements in red/brown/orange), NDPK-D only binds to MIM, which maintains phosphotransfer activity but prevents lipid transfer. NDPK-D regenerates NTP (mainly GTP) in the intermembrane space (IMS), in particular for local use, e.g. by the interacting GTPase OPA1. NDPK-D also channels ADP via adenylate translocase (ANT) into the matrix space for stimulation of oxidative phosphorylation (OXPHOS). Right: In the lipid transfer mode (elements in light and dark blue/magenta), the symmetrical NDPK-D hexamers are fully membrane-bound, i.e. attached simultaneously to MIM and MOM, thus tightly cross-linking both membranes. This inhibits phosphotransfer activity, but allows for intermembrane lipid transfer, in particular of cardiolipin, whose exposure at the mitochondrial surface is suggested to have signaling character. The mechanism responsible for switching between the two modes is currently unknown, but may depend on the availability/accessibility of CL and other anionic phospholipids in the MIM outer leaflet and the MOM inner leaflet, or interacting proteins like OPA1. (B) Octameric MtCK may function in a similar way as NDPK-D in phospho- and lipid transfer as suggested by in vitro experiments (Epand et al., 2007a; Schlattner et al., 2009). In its phosphotransfer (kinase) function, MtCK phosphorylates creatine imported from the cytosol to generate phosphocreatine that is again exported for usage outside mitochondria. However, in contrast to NDPK-D, phosphotransfer activity is not strongly affected in the fully membrane-bound and lipid-transfer competent state, so both processes may occur simultaneously.

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model for NDPK-D function has been proposed, where the NDPK-D complex works either in a phosphotransfer or a lipid transfer mode (Fig. 4A). An intermembrane transfer of CL from MIM to MOM in intact mitochondria has been repeatedly reported for the initial steps of apoptosis (Chu et al., 2013; Garcia Fernandez et al., 2002). In the HeLa model overexpressing NDPK-D, increased CL-content in MOM indeed sensitized the cells to rotenone-induced apoptosis (Schlattner et al., 2013). This suggests that NDPK-D has switched into the lipid transfer mode to facilitate CL externalization toward the mitochondrial surface where CL then serves as pro-apoptotic signal.

3.2. MtCK Mitochondrial isoforms of the creatine kinase (CK) family comprise sarcomeric MtCK (sMtCK) expressed in skeletal and cardiac muscle, and ubiquitous MtCK (uMtCK) expressed in different organs and cell types, in particular in brain, kidney and various epithelia (reviewed in Schlattner et al., 2006a,b; Wallimann et al., 2011). They are imported into the IMS via a mitochondrial targeting sequence and assemble into cuboidal octamers. Under certain conditions like, e.g. after oxidative modifications, octamers can dissociate into stable dimers (Soboll et al., 1999; Schlattner et al., 2000), particularly well studied for cell damage induced by the anthracycline anti-cancer drugs (Tokarska-Schlattner et al., 2002, 2007). Driven by mitochondrially generated ATP, the reversible MtCK reaction is directed toward the generation of phosphocreatine from creatine (Fig. 4B). These two metabolites are exchanged with the cytosol via the MOM protein VDAC (voltage dependent anion channel) that also interacts with MtCK (Schlattner et al., 2001). For cellular uptake of creatine into most cells, a specific plasma membrane transporter is required (Speer et al., 2004; Christie, 2007). Phosphocreatine generated by MtCK (and also by cytosolic creatine kinases) provides a cellular energy buffer for maintaining global ATP levels. Together with cytosolic CKs, MtCKs are also involved in an intricate energy shuttle system linking cellular sites of ATP generation with sites of ATP consumption (Schlattner et al., 2002; Wallimann et al., 2011). This is due to the specific localization of a portion of CK isoforms in defined, subcellular microcompartments that generate ATP (mitochondrial oxidative phosphorylation, glycolysis) or consume ATP (ATPases, ATP-gated ion channels, ATP-dependent signaling events etc.) (Lenz et al., 2005; Schlattner et al., 2006a,b; Wallimann et al., 2011). The octameric MtCK complexes (Fig. 4B) share several properties with the hexameric NDPK-D: (i) the large symmetrical homooligomeric structure (Eder et al., 2000; Fritz-Wolf et al., 1996), (ii) lipid binding motifs in each monomer, consisting of three positively charged amino acids that interact with high affinity with anionic phospholipids, mainly CL (Schlattner et al., 2004; Schlattner and Wallimann, 2000b), (iii) binding motifs exposed at both rotation-symmetrical opposite faces of the cuboidal complex, able to cross-link two different membranes (Schlattner and Wallimann, 2000b; Eder et al., 2000) and (iv) the ability to transfer model lipids between the two membranes (Epand et al., 2007a). Dimerization of the MtCK octamer reduces CL binding (Schlattner and Wallimann, 2000a) and thus also the lipid transfer capability. Interestingly, MtCKs and NDPK-D show quite inverse expression patterns: MtCKs are virtually absent in liver, where NDPK-D is highest, while high expression is found for sMtCK in muscle and uMtCK is brain, where NDPK-D is lowest (Lacombe et al., 2009). Taken together, these data are suggestive for equivalent roles of MtCK and NDPK-D in intermembrane CL transfer (Schlattner et al., 2009). In addition MtCK binding to model membranes leads to lipid phase separation and clustering of cardiolipin (Epand et al., 2007b).

3.3. MINOS/MICOS/MitOS complex A large heterooligomeric protein complex anchored in the MIM and enriched at cristae junctions has recently been identified by different groups and named MINOS (Alkhaja et al., 2012; von der Malsburg et al., 2011), MICOS (Harner et al., 2011) or MitOS (Hoppins et al., 2011). This contact site complex has been reviewed quite extensively (van der Laan et al., 2012; Zerbes et al., 2012) and will thus be presented here only shortly. The MINOS complex contains 6 proteins in yeast (mammalian orthologues in brackets; for abbreviations see Fig. 3): the core components Fcj1 (mitofilin) and Mio10 (MINOS1), as well as the additional Aim5, Aim13 (CHCHD4/MINOS3) and Aim37-Mio27 (MOMA1). The MINOS complex can interact with various integral MOM proteins to from MIM/MOM contact sites, including protein translocases (TIM, SAM), the pore-forming VDAC, and the MOM fusion protein Ugo1. Further structural and/or functional interactions may occur with the MOM/MAM contacts like ERMES in yeast (see below). The complex also maintains mitochondrial morphology by supporting the cristae junctions that connect the IMS inner boundary membrane to the cristae membrane. There is some evidence that MINOS complexes are involved in intermembrane lipid movements. MitOS genes show a strong genetic interaction with ERMES and genes in phospholipid biosynthesis (Hoppins et al., 2011). However, MINOS mutants with aberrant mitochondrial morphology did not display changes in mitochondrial phospholipid distribution (Bohnert et al., 2012; Harner et al., 2011). Thus, this complex may not be considered as an active compound in CL transport. 3.4. Other MIM/MOM candidate contact site proteins: ATAD3 Besides the large homo- and heterooligomeric complexes described before, a further protein that can form MOM/MIM contact sites and may even participate in tethering of mitochondria to ER is the ATPase family AAA Domain-containing protein 3 (ATAD3; reviewed in Li and Rousseau, 2012). Although already discovered in 2003 as a c-Myc gene target (Zeller et al., 2003) and shown to possess in silico ATPase structure, its in vivo functions have remained mostly elusive so far. ATAD3 is localized in mitochondria (Schaffrik et al., 2006) and, like many other ATPases, can form homooligomeric structures up to hexamers (Gilquin et al., 2010a). Proteomic approaches located ATAD3 in MIM (Da Cruz and Martinou, 2008; Da Cruz et al., 2003), but its membrane insertion topology seems to be more complex. The C-terminal half, constituting the ATPase core domain, locates within the mitochondrial matrix, while the N-terminal half supposed to provide a more specific function locates to the IMS and may interact also with MOM or even cytosolic partners (Gilquin et al., 2010b; Hubstenberger et al., 2010; Li and Rousseau, 2012). Although direct evidence is still lacking, ATAD3 may thus participate in a transmembrane complex joining MIM/MOM and facilitating lipid transfer. In support of this, Chow and colleagues showed an interaction of ATAD3 with proteins of MOM/MAM contact sites like the fusion/fission proteins Mfn2 and Drp1 (see Section 4.2; Chiang et al., 2012). ATAD3 also interacts specifically in a Ca2+ dependent manner with cytosolic S100B (Gilquin et al., 2010a; Li and Rousseau, 2012), a protein also described as a potential PS transfer protein (see Section 5.2). Knock-down studies in primary and immortalized cultured cells showed that ATAD3 is not only essential for maintaining the mitochondrial network (Gilquin et al., 2010b; Hoffmann et al., 2009), but also important for lipid-requiring mitochondrial biogenesis (He et al., 2012) and cholesterol transfer from ER to mitochondria (Gilquin et al., 2010b; Issop et al., 2013; Rone et al., 2012). ATAD3 knock-down

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inhibits mitochondrial steroidogenesis that depends on cholesterol import. Further, Rone et al. (2012) found ATAD3 in a mitochondrial membrane super-complex able to bind cholesterol. ATAD3 appears in all pluri-cellular organisms as a single gene and has evolved only in primates into three ATAD3 encoding genes. It is expressed in all tissues and cells studied so far, with increased levels related to cancer initiation and progression, chemoresistance and apoptosis (Chen et al., 2011b; Fang et al., 2010; Gires et al., 2004; Huang et al., 2011; Hubstenberger et al., 2010; Schaffrik et al., 2006). ATAD3 is also essential for early embryogenesis of C. elegans (Hoffmann et al., 2009; Kamath and Ahringer, 2003; Piano et al., 2002; Simmer et al., 2003; Sonnichsen et al., 2005), D. melanogaster (Gilquin et al., 2010a; Guertin et al., 2006), and mouse (Goller et al., 2013). First effects of reduced ATAD3 expression in worm or mouse occur in intestinal fat tissue and gonads or during trophoblast development, respectively, at a time where mitochondrial biogenesis is initiated (Goller et al., 2013; Hoffmann et al., 2009). Taken together, all available data support a pleiotropic role of ATAD3 in fundamental mitochondrial morphology, biogenesis and function linked to cell growth. How exactly ATAD3 can support such functions at a molecular level, including putative lipid transfer, is still not understood. It will be important to further examine these functions by appropriate in vitro systems with recombinant ATAD3 and putative partners (Li et al., 2012). 4. MOM/MAM contact site proteins and phospholipid transfer Much progress has been made during recent years in respect to protein complexes that tether mitochondria to ER (Fig. 3; see also for abbreviations). Contact sites between MOM and MAM emerged not only as essential for transfer of lipids, but also for exchange of calcium (Rizzuto et al., 1993; Szabadkai et al., 2006) and most surprisingly for mitochondrial dynamics. These membrane junctions seem to represent preferential places of mitochondrial fission (Friedman et al., 2011), they contain the MOM GTPase Miro involved in mictotubule-based mitochondrial movements (Wang and Schwarz, 2009), and they may be involved, at least in budding yeast, in mitochondrial inheritance by anchoring the organelle to ER in the budding cell (Swayne et al., 2011). A short review on MOM/MAM contact sites has been published recently (Kornmann, 2013), and we will only highlight some essential features here. 4.1. Yeast: ERMES complex A multi-protein complex linking mitochondria and ER has been characterized in a yeast screen for mutants whose growth can only be rescued by a synthetic mitochondria-ER tether (Kornmann et al., 2009). This complex termed ER-mitochondria encounter structure (ERMES) shows a punctuate pattern along the mitochondria/ER interfaces. It is composed of mitochondrial and ER membrane proteins, additional cross-linking proteins, and optional regulatory proteins like the Miro GTPase Gem1 (Fig. 3; reviewed in Kornmann and Walter, 2010; Michel and Kornmann, 2012). However, some functions of mitochondria/ER interfaces are preserved in mutants lacking ERMES core components. A recent study showed that ERMES and Gem1 have no direct role in the transport of PS from the ER to mitochondria, necessary for mitochondrial PE synthesis (Nguyen et al., 2012), but it remains an open question whether the same applies for the CL-precursor PA. Thus, other mitochondria/ER contact site structures may exist in yeast, like homodimer formation of the peripheral membrane protein Mmr1 (Swayne et al., 2011). In metazoan, there are no homologues of ERMES core components, and mitochondria/ER contacts depend on various other protein complexes that have been more or less well described during recent years.

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4.2. Metazoa: Mfn1/2, Grp75, and others Mitochondria/ER tethers in metazoan are formed by multiple, mostly dimeric protein complexes (Fig. 3). The MOM mitofusins Mfn1 and Mfn2 can interact with a fraction of Mfn2 that is localized in the MAM membrane (de Brito and Scorrano, 2008), and MOM fission protein Fis1 interacts with MAM protein Bap31 (Iwasawa et al., 2011), suggesting that these sites play a role in mitochondrial fission/fusion. The cytosolic chaperone Grp75 is able to cross-link the MAM IP3 receptor with the MOM porin VDAC (Szabadkai et al., 2006), participating in ER Ca2+ -release and mitochondrial calcium import, respectively. Calcium homeostasis seems to be also the main function of mitochondria/ER contact sites formed by VABP and PTPIP51 (De Vos et al., 2012). Taken together, specific functions have been assigned to these different types of metazoan contact sites, but it is unknown so far whether they are also involved in phospholipid transfer. 4.3. Other MOM/MAM candidate contact site proteins NDPK-C, another member of the NDPK family encoded by the NME3 gene, has been reported to be, at least partly, associated with mitochondria (Negroni et al., 2000). NDPK-C possesses a 17 amino acid N-terminal hydrophobic peptide which is not a canonical mitochondrial targeting sequence but could anchor the protein to membranes (Barraud et al., 2002). Indeed, a NDPK-CGFP fusion protein was observed to be associated with MOM (MLL, unpublished results). Data on NDPK-C are scarce, but due to its symmetrical hexameric structure similar to NDPK-D, it is tempting to propose that it could be involved in bridging MOM with MAM. However, NDPK-C possesses a negatively charged residue at the position equivalent to R90 involved in CL binding of NDPK-D, so a different lipid interaction partner may be involved. 5. Specific lipid transfer proteins Non-vesicular lipid transport within a cell is generally catalyzed by specific lipid transport proteins (reviewed in Helle et al., 2013; Lev, 2010, 2012). These proteins are able to do both, extracting a lipid from the membrane bilayer and deliver it to another. Classical lipid transfer proteins contain one of the known lipidtransport domains that provide a hydrophobic pocket to shield the hydrophobic acyl chains from the aqueous environment. Lipid transfer proteins generally function as lipid exchanger rather than as unidirectional transporter. It is thought that specificity of the process is provided by membrane contact sites, while the directionality of transfer depends on energy-requiring processes or simply the existing concentration gradients. Although several classes of lipid transfer proteins have been described for phospholipid transfer between different cellular compartments, those involved at MIM/MOM and MOM/MAM contacts are mostly unknown. More recently, some candidates emerged for MIM/MOM lipid transfer activity (Fig. 3). NDPK-D and MtCK may provide not only a simple intermembrane contact, but also “alternative” lipid transfer routes (see Sections 3.1 and 3.2, as well as Fig. 4). The capacity of membrane-bound NDPK-D to lead to CL enrichment in MOM has been demonstrated recently (Schlattner et al., 2013). Another more classical lipid transfer protein described in mitochondria is the Ups/PRELI family with several members in most organisms. 5.1. Ups/PRELI family Transfer of specific phospholipids between MOM and MIM is catalyzed by protein complexes involving members of the Ups1/PRELI-like protein family localized in the IMS (reviewed in Tatsuta et al., 2014). In yeast, the family comprises Ups1, Ups2

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and Ups3 (unprocessed 1–3) (Tamura et al., 2009), while mammals express four PRELI proteins named PRELI1, PRELI2 (protein of relevant evolutionary and lymphoid interest 1 and 2), SLMO1 and SLMO2 (slowmo homologue 1 and 2) (Potting et al., 2013; Tatsuta et al., 2014). It was first shown in yeast that mitochondrial metabolism of phospholipids like CL and PE depends on Ups1 and Ups2 (Gep1) that are able to transfer the respective precursors PA and PS from MOM to MIM, and possibly re-export synthesized PE again toward MOM (Connerth et al., 2012; Tamura et al., 2012). Yeast cells lacking Ups1 have reduced CL synthesis, and this loss can be complemented by expression of mammalian PRELI1. Although there is no sequence similarity, structure modeling of these proteins predicts the presence of a lipid-transport domain similar to PI transfer proteins. Ups1 and Ups2 seem to maintain a lipid transfer cycle that is regulated by stabilization and degradation of these Ups proteins (Tatsuta et al., 2014). As intrinsically unstable proteins, both Ups are rapidly degraded by mitochondrial metalloproteases associated with MIM, either Yme1 (cleaving both Ups1 and Ups2) or Atp23 (only Ups1). In contrast, when imported into IMS, both Ups are stabilized and protected against proteolysis by binding to another IMS protein, Mdm35 (Potting et al., 2010; Tamura et al., 2010). Binding to membranes again tends to destabilize Ups1/2. A homologous mechanism exists in mammals, where PRELI proteins entering IMS, bind to the Mdm35-homologue TRIAP1 and are protected from proteolysis by the i-AAA protease YME1L (Potting et al., 2013). Based on these properties, a current model for PA transfer (Tatsuta et al., 2014) proposes that Ups1/PRELI1 bound to donor membrane extracts PA and detaches it from membrane by forming a stabilizing complex with Mdm35/TRIAP1. Ups1/PRELI1 then binds to anionic phospholipids in the acceptor membrane, dissociates from Mdm35/TRIAP1 and inserts PA into the bilayer. Then, Ups1/PRELI1 returns back to the adjacent membrane in loaded or empty form. Since in vitro PA transfer is bi-directional, it may occur between MOM and MIM in both directions, and would be rather driven by the PA concentration gradient. Conversion of PA into CL in MIM could create the sink to favor unidirectional PA transfer to MIM. In addition, at a certain threshold of synthesized CL occurring at the outer leaflet of MIM, the destabilized membrane-bound form of Ups1/PRELI1 would be favored and become degraded by the metalloproteases, thus limiting further PA import. Ups1-Mdm35 and PRELI-TRIAP1 complexes facilitate specifically PA transfer between liposomes in vitro, although binding occurs to all major anionic phospholipids, suggesting that binding and transfer are distinct processes. Deletion of Ups2 leads to reduced mitochondrial PE levels, proposing a role of Ups2 in mediating PS transfer, possibly by a mechanism similar to what has been proposed for Ups1/PRELI1. Finally, Ups3 seems to share redundant functions with Ups2. 5.2. Other candidate lipid transfer proteins Some further mitochondrial proteins have been described to show lipid transfer activity in vitro or to alter mitochondrial phospholipid levels, mostly by affecting exchange between MOM and other cellular membranes. However, none of them has been specifically observed so far to transfer CL. The abundant pro-apoptotic Bid, a Bcl-2 family member, and its cleaved product tBid transfer PA and PG between liposomes in vitro, and they may transport these and possibly also other negatively charged lipids between MAM and MOM (Degli Esposti, 2002; Esposti et al., 2001). In various types of plants, non-specific lipid transfer proteins are known since long (Kader, 1996). Among the various reported functions, they can apparently also facilitate lipid exchange between cellular membranes and mitochondria. Non-specific lipid transfer

proteins accept a broad range of phospholipids (PC and PI, to lesser extents PE or PG), but not CL. By genetic evidence in yeast, an E3 ubiquitin ligase complex has been involved in affecting PS and PE transfer between ER and mitochondria (Voelker, 2003). One of its subunits, Met30p, affects mitochondrial PE levels, and another, Met4p, has been proposed to disturb PS transfer to mitochondria (Choi et al., 2006; Schumacher et al., 2002; Thomas et al., 1995). The complex is supposed to interact with hitherto unknown proteins in MAM and MOM. Interestingly, PS transfer to mitochondria was reported to be also accelerated by the S100B protein (Kuge et al., 2001), a binding partner of ATAD3 involved in MIM/MOM contacts (see Section 3.4), thus suggesting a continuity of lipid transfer events. In yeast, genetic screening identified further proteins potentially involved in phospholipid transfer like R41 that affects PS transfer to MIM (Emoto et al., 1999). In the context of MAM/MOM lipid transfer, it is also remarkable that proteins involved in shaping the ER structure facilitate such transfer (Voss et al., 2012). These proteins include reticulons, reticulon-like proteins, and atlastins (dynamin-like GTPases) in mammals and Sey1p in yeast. Apparently their function is necessary to maintain optimal MAM/MOM contacts provided in yeast by the ERMES complex (see Section 4.1).

6. Intramembrane lipid transfer: flippases and scramblases A characteristic of biological membranes is their transbilayer asymmetry. The origin and maintenance of this asymmetry has been extensively studied for many years (reviewed in van Meer, 2011). One factor in determining asymmetry is the site of lipid synthesis. The asymmetry is a crucial factor for the structure of the membrane and the interaction among membrane components, either among lipids to form lipid domains or between lipids and proteins to modulate the structure and activity of the protein. In addition, the appearance of specific anionic lipids on the surface of mitochondria or cells provides a signal for removal of the structure. Like with intermembrane lipid transfer, lipid movements between leaflets of a membrane are unlikely occurring only spontaneously (Fig. 2C). They are also catalytically supported by specific enzymes, flippases and scramblases (Fig. 2D). Both types of proteins react to membrane stress (Chu et al., 2013; Devaux et al., 2008). Flippases actively translocate the aminophospholipids PS and PE to the cytosolic surface of the plasma membrane. This is a process requiring energy in the form of ATP hydrolysis. Flippases have an important role in maintaining the asymmetry of the plasma membrane and keeping the anionic lipid, PS on the cytoplasmic surface. Exposure of PS on the exterior of cells is a signal for elimination of the cell by phagocytosis as well as being used to initiate blood coagulation. In contrast to flippases, scramblases may promote the passive movement of phospholipids down a concentration gradient. They can catalyze the movement of lipids in either direction across the membrane bilayer. This results in some loss of phospholipid asymmetry since lipids can only be translocated from a surface in which they are at higher concentration to the opposite surface. This is unlike flippases that can create a concentration gradient through the use of the energy of ATP hydrolysis. The problem with ascribing a phospholipid translocating activity to scramblases is that there is much non-specific translocating activity by membrane proteins. Because of this fact, biological membranes can accelerate the nonspecific flip-flop of lipids by orders of magnitude, compared with pure phospholipid liposomes devoid of protein. One specific aspect of scamblases is that they require Ca2+ for activity. This can give them a specific function of exposing anionic lipid to the cell surface for recognition during cell injury or membrane damage, where

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intracellular Ca2+ increases which is otherwise maintained at a very low level. Scramblases in general are known to transfer lipids from a higher concentration on one monolayer of a bilayer to the other monolayer. However, at least in the case of scramblase 3 (PLS3), there is evidence that it can facilitate the transfer of lipid from one membrane bilayer to another. At least functionally it has been shown that PLS3 promotes the MIM-MOM movement of CL (Chu et al., 2013; Liu et al., 2008). Recently it has also been found that PLS3 can be secreted and may promote intercellular transfer of lipid (Inuzuka et al., 2013). Although PLS3 affects lipid movement between mitochondrial membranes to promote apoptosis (Liu et al., 2008; Ndebele et al., 2008; Van et al., 2007), little of the protein has been found in mitochondria with immunofluorescent staining ((Inuzuka et al., 2013) and Kagan, personal communication). The reason for this discrepancy is not known but may be a function of the exposure of particular epitopes of the protein. If it is assumed that PLS3 is on the MIM, then as a scamblase it would promote the movement of CL from the matrix side of the MIM, where it is synthesized, to the IMS side of this membrane. This may be sufficient to initiate the translocation of CL from MIM to MOM through several possible mechanisms. PLS3 can promote the movement of CL from MIM to MOM where it may act as a signal for mitophagy (Chu et al., 2013) or apoptosis (Liu et al., 2008; Ndebele et al., 2008; Van et al., 2007). However, several alternative mechanisms may explain such an effect, including the protein facilitating direct transfer of CL between membranes, facilitating flip-flop across the inner mitochondrial membrane with other proteins moving the lipid between membranes or a more indirect role of PLS3 acting in a signal transduction system to promote the activity or expression of other proteins that actually carry out the transfer. Activities of scramblase 1 (PLS1) that are independent of lipid transfer have been found. PLS1 translocates to the nucleus and functions as a transcription factor with DNA binding ability (Chen et al., 2011a; Zhou et al., 2005). Modeling of PLS1 suggests that this and other PLS isoforms belong to the family of Tubby-like proteins that function as transcription factors (Bateman et al., 2009). 7. Perspectives Identification of proteins and protein complexes that form contact sites between mitochondrial membranes and adjacent ER membranes and which are involved in inter- and intramembrane lipid transfer has prepared ground to study molecular mechanisms and physiological functions of lipid trafficking and lipid sorting in mitochondria. Among others, “ancient” oligomeric kinases, NDPKD and MtCK, seem to have dual functions in supporting also intermembrane CL transfer. It also emerges that specific lipid distribution is not only due to biosynthetic pathways or involved in structural aspects of membrane protein function and mitochondrial morphology. Rather, CL trafficking linked to membrane asymmetries and their collapse, as well as CL remodeling and CL oxidative modifications seem to play important roles in signaling mitophagy and apoptosis. Future studies will have to fully unravel the intricate role of CL/phospholipid trafficking for mitochondrial and cell function. References Adams, V., Bosch, W., Schlegel, J., Wallimann, T., Brdiczka, D., 1989. Further characterization of contact sites from mitochondria of different tissues: topology of peripheral kinases. Biochim. Biophys. Acta 981, 213–225. Alkhaja, A.K., Jans, D.C., Nikolov, M., Vukotic, M., Lytovchenko, O., Ludewig, F., Schliebs, W., Riedel, D., Urlaub, H., Jakobs, S., Deckers, M., 2012. MINOS1 is a conserved component of mitofilin complexes and required for mitochondrial function and cristae organization. Mol. Biol. Cell 23, 247–257.

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