Interaction of NDPK-D with cardiolipin-containing membranes: Structural basis and implications for mitochondrial physiology

Biochimie 91 (2009) 779–783

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Review

Interaction of NDPK-D with cardiolipin-containing membranes: Structural basis and implications for mitochondrial physiology Marie-Lise Lacombe a, *, Malgorzata Tokarska-Schlattner b, Raquel F. Epand c, Mathieu Boissan a, Richard M. Epand c, Uwe Schlattner b, ** a b c

INSERM UMRS_893, UMPC Universite´ Paris 06, 27 rue Chaligny, 75012 Paris, France INSERM U884, Universite´ Joseph Fourier, Laboratoire de Bioe´nerge´tique Fondamentale et Applique´e, 38041 Grenoble, France McMaster University Health Sciences, Hamilton, Ontario L8N 3Z5, Canada

a r t i c l e i n f o

a b s t r a c t

Article history: Received 23 December 2008 Accepted 18 February 2009 Available online 28 February 2009

Nucleoside diphosphate kinases (NDPKs/Nm23), responsible for intracellular di- and tri-phosphonucleoside homeostasis, play multi-faceted roles in cellular energetic, signaling, proliferation, differentiation and tumor invasion. The mitochondrial NDPK-D, the NME4 gene product, is a peripheral protein of the inner membrane. Several new aspects of the interaction of NDPK-D with the inner mitochondrial membrane have been recently characterized. Surface plasmon resonance analysis using recombinant NDPK-D and different phospholipid liposomes showed that NDPK-D interacts electrostatically with anionic phospholipids, with highest affinity observed for cardiolipin, a phospholipid located mostly in the mitochondrial inner membrane. Mutation of the central arginine (R90) in a surface exposed cationic RRK motif unique to NDPK-D strongly reduced phospholipid interaction in vitro and in vivo. Stable expression of NDPK-D proteins in HeLa cells naturally almost devoid of this isoform revealed a tight functional coupling of NDPK-D with oxidative phosphorylation that depends on the membrane-bound state of the enzyme. Owing to its symmetrical hexameric structure exposing membrane binding motifs on two opposite sides, NDPK-D could bridge liposomes containing anionic phospholipids and promote lipid transfer between them. In vivo, NDPK-D could induce intermembrane contacts and facilitate lipid movements between mitochondrial membranes. Most of these properties are reminiscent to those of the mitochondrial creatine kinase. We review here the common properties of both kinases and we discuss their potential roles in mitochondrial functions such as energy production, apoptosis and mitochondrial dynamics. Ó 2009 Elsevier Masson SAS. All rights reserved.

Keywords: Mitochondria Oxidative phosphorylation Phospholipid Nm23 Creatine kinase

1. Introduction Nucleoside diphosphate kinases (NDPKs) catalyze the exchange of g-phosphate between di- and triphosphonucleosides and participate in the regulation of intracellular nucleotide homeostasis. They mainly utilize ATP, formed by oxidative phosphorylation, as the phosphate donor to synthesize the other triphosphonucleosides, in particular GTP [1]. It was proposed that NDPKs participate in high-energy phosphoryl transfer and signal communication in concert with other nucleotide metabolizing

Abbreviations: ANT, adenine nucleotide translocator; CL, cardiolipin; MtCK, mitochondrial creatine kinase; NDPK, nucleoside diphosphate kinase. * Corresponding author. Tel.: þ33 1 40 01 13 55; fax: þ33 1 40 01 13 52. ** Corresponding author. Tel.: þ33 4 76 51 46 71; fax: þ33 4 76 51 42 18. E-mail addresses: [email protected] (M.-L. Lacombe), uwe. [email protected] (U. Schlattner). 0300-9084/$ – see front matter Ó 2009 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.biochi.2009.02.006

enzymes such as adenylate kinases, creatine kinases and glycolytic enzymes [2]. NDPKs are involved in multiple physiological and pathological cellular processes such as differentiation, development, metastatic dissemination and cilia functions [3,4] through largely unknown mechanisms. Given the low substrate selectivity of NDPKs, it is assumed that specificity could arise from the presence of different isoforms at different sub-cellular localizations. Indeed, NDPK activity has been found associated with different cellular compartments, such as cytosol, nucleus, plasma membrane and mitochondria but little is known about their respective role within the cell. Up to ten genes, known as NME or NM23, encoding NDPK or NDPK-like proteins have now been identified [3,4]. NDPKA to -D (or Nm23-H1 to -H4, where H stands for human) show high sequence homology, are all hexameric and possess unambiguous NDPK activity [5]. The most intensely studied, NDPK-A and -B play a key role in tumor progression and metastasis dissemination [6–8]. Recent data show that NDPK-D, product of the NME4 gene,

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is a mammalian mitochondrial NDPK associated with the inner membrane [9,10]. This review will focus on the newly characterized aspects of these interactions of NDPK-D. Some similarities between NDPK-D and the mitochondrial isoform of creatine kinase (MtCK [11]) will be discussed. 2. The mitochondrial NDPKs An NDPK enzyme activity specific to mitochondria was described in 1955 [12], two years after the discovery of the enzyme. NDPK activity was reported in both the matrix and the extra-matrix compartments and also associated with the contact sites connecting the inner and outer membranes [13,14]. The submitochondrial localisation was very variable, depending on the species and the tissue examined. In mammals, a prominent matrix activity was found in the heart while in the liver the activity was mainly associated with an extra-matrix compartment [15]. The membrane-bound or soluble state of the enzyme remained undefined in the studies. Many functions have been proposed for mitochondrial NDPK. In the matrix, the enzyme can provide NTP as precursors of nucleic acid synthesis, GTP for protein synthesis and ATP to fuel the chaperones of the protein import machinery [16]. The enzyme was also proposed to be associated with the Krebs cycle, where it would synthesize ATP at the expense of GTP provided through succinyl thiokinase. Moreover, matrix NDPK has been involved in short chain fatty acid catabolism [15,17] and, recently, in iron homeostasis by furnishing GTP [18]. In the intermembrane/cristae space, NDPK was proposed to supply cellular NTP at the expense of ATP, synthesized by oxidative phosphorylation and NDP, diffusible from cytoplasm through the outer membrane [19]. In mammals, the only NDPK possessing a specific mitochondrial targeting sequence is NDPK-D [9,20]. Two other human genes, NME3 (encoding NDPK-C also named DR-nm23) and NME6, have been reported to encode proteins that are, at least partially, associated with mitochondria [21,22]. However, for these proteins, neither a specific mitochondrial targeting sequence could be detected nor an exact submitochondrial localisation was reported. Only NDPK-C possesses a 17 aa N-terminal hydrophobic peptide, which could anchor the protein to membranes [23]. NDPK-C inhibits granulocyte differentiation and induces apoptosis of 32Dc13 myeloid cells [24]. The NME6 gene product could be involved in cell cycle progression [22]. Specific mitochondrial NDPKs have been identified in other organisms such as Dictyostelium discoideum [25] and plants [26] and, since then, numerous mitochondrial NDPK sequences were deposited in data banks. 3. NDPK-D NDPK-D is ubiquitously expressed, with the highest expression in liver, kidney, bladder and prostate (Fig. 1A). The kinase occurs as a peripheral protein bound to mitochondrial membranes through an electrostatic interaction [9]. Subfractionation of rat liver and HEK 293 cell mitochondria revealed that NDPK-D is essentially bound to the inner membrane. Combination of site-directed mutagenesis and surface plasmon resonance spectroscopy using model liposomes containing anionic phospholipids has shown an interaction between a cationic motif (Arg89–Arg90–Lys91), unique to NDPK-D and located at the surface of the hexamer [9,10] and cardiolipin (CL), the predominant anionic phospholipid of the mitochondrial inner membrane. Mutation of the central arginine (R90D) strongly reduced the NDPK-D/phospholipid interaction in model liposomes in vitro or with mitochondrial membranes in HeLa cells in vivo [10]. Interestingly, the cationic motif is located within a loop, connecting helices aA and a2, which is mobile unless

stabilized by substrate binding and which contains the most divergent part of the NDPK sequences [27]. Orientation of NDPK-D at the inner mitochondrial membrane was analyzed by the accessibility of the enzyme to either substrates or antibodies. These studies showed that NDPK-D exhibits a preferred orientation towards the intermembrane space. However, a subpopulation of proteins was only accessible to substrates or antibodies if the inner membrane was lysed by detergent, indicating that the enzyme could also face the matrix or might be hidden within complexes or cristae structures. In HeLa cells, with naturally almost undetectable NDPK-D, stable expression of wild type but not of R90D mutant led to membrane-bound enzyme in vivo. Orientation of NDPK-D towards intermembrane space was corroborated by respiratory analysis, indicating that enzyme present in the intermembrane space can use ATP generated by oxidative phosphorylation and locally regenerate ADP which enters the matrix space to stimulate oxidative phosphorylation (Fig. 2). Coupling of the NDPK reaction to oxidative phosphorylation was demonstrated in rat liver mitochondria [19,28], however it was not clear which isoform is involved. Recently, it was shown that respiration of purified mitochondria of HeLa cells overexpressing the wild-type NDPK-D could be significantly stimulated by the NDPK substrate TDP. This indicates local regeneration of ADP in the mitochondrial intermembrane space and a functional coupling of NDPK-D with oxidative phosphorylation. Interestingly, respiratory stimulation by TDP was much weaker in mitochondria from cells overexpressing the binding-deficient R90D mutant yet catalytically equally active. Thus, the membrane-bound state of NDPK-D is important for full functional coupling with respiration [10]. Corroborating such a model, plant mitochondrial NDPK was found associated with the adenine nucleotide translocator (ANT) [29]. Owing to its symmetrical hexameric structure, NDPK-D exposes three basic membrane binding motives on two opposite faces [9], suggesting that it could promote intermembrane contacts. Indeed, NDPK-D cross-linked anionic phospholipid-containing liposomes in vitro while the R90D mutant did not [10,30]. As further outlined below, NDPK can also mediate lipid transfer between model liposomes with no fusion between the bilayers [30]. These data shed a new light on yet undescribed functions of a mitochondrial NDPK. 4. The mitochondrial kinases (NDPK-D and MtCK): common properties Many properties of NDPK-D are reminiscent to those reported earlier for another kinase of the mitochondrial intermembrane space, the mitochondrial creatine kinase (MtCK) [31]. They both use mitochondrially generated ATP with the ultimate goal to maintaining proper nucleotide pools, are located in the intermembrane/ cristae space, show high affinity binding (20–50 nM) to anionic phospholipids, in particular CL, and have symmetrical oligomeric structures capable to cross-link membranes [9,10,30,32]. CL binding loops of the two enzymes are mobile and therefore susceptible to provide the flexibility necessary for docking to CL. Binding to CL results in a functional interaction with inner membrane ANT, probably by forming proteolipid complexes that allow privileged exchange of metabolites (channeling) and regulation of mitochondrial respiration. CL interaction of both kinases affects structure and function of mitochondrial membranes. MtCK is able to cluster CL in model membranes, a process dependent on the octameric form of the enzyme, not observed with the dimer [33]. Whether NDPK-D could also be involved in CL clustering deserves further study. For MtCK, there is also experimental evidence that cross-linking of membranes occurs in vivo, leading to contact sites between outer

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Fig. 1. Expression profile of mitochondrial kinases. (A) Expression of NDPK-D in different tissues analyzed using the Human RNA Master Blot from Clontech probed by hybridisation to the NME4 cDNA prepared as described in [20]. (B) Comparison of relative expression of NDPK-D and two other kinases of the mitochondrial intermembrane space: creatine kinase (sarcomeric, sMtCK, and ubiquitous, uMtCK) and adenylate kinase (AK2) in liver, prostate, brain, skeletal muscle and heart, calculated from data available at: http://symatlas. gnf.org. Data references are: uMtCK: 202712_s_at; sMtCK: 205295_at; AK2: mean for 208967_s_at, 205996_s_at, 212172_at, 212173_at, 212174_at, 212175_at, and NDPK-D: 212739_s_at. For each kinase, the mRNA levels were normalized to the organ showing the maximal expression.

and inner mitochondrial membrane [34], while for NDPK-D this is likely, given the in vitro evidences [10,30]. Such contact sites may be involved in yet another common function of the two kinases, promotion of transmembrane lipid transfer [30]. CL is synthesized at the mitochondrial inner membrane [35] and represents its major constituent, but small amounts are also detectable in the outer mitochondrial membrane [36]. Thus, lipid transfer away from the inner membrane must occur, and has indeed been observed during apoptosis where it may represent a crucial signal [37–41]. On the inner membrane, CL controls retention of cytochrome C in the cristae while apoptotic stimuli induce CL oxidation and cytochrome C release [42]. On the outer membrane, CL acts as mitochondrial receptor for BID, regulates oligomerization of proapoptotic BAK and BAX, and, as was shown very recently, forms an activating platform for caspase 8 [43]. Although several proteins such as scramblases are involved in intermembrane lipid translocation, a role of both

oligomeric mitochondrial kinases in this process deserves further studies. Some similar functions of NDPK-D and MtCK isoforms (sarcomeric and ubiquitous isoforms, sMtCK and uMtCK, respectively) are also suggested by their expression pattern in different organs (Fig. 1B). Although such a comparison is limited by the heterogeneity of some organs, the data suggest that the expression of NDPKD and MtCK isoforms is inversely related. In particular in liver, NDPK-D levels are very high, while the MtCK is practically absent. The inverse relation is observed in heart, expressing high levels of MtCK and relatively little NDPK-D. In contrast to these large oligomeric and CL-binding kinases, another kinase of the intermembrane space, the small monomeric and soluble adenylate kinase isoform 2, is ubiquitously expressed in all tissues. We hypothesize that NDPK-D and MtCK may replace each other for some functions, as e.g. lipid transfer.

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Fig. 2. NDPK-D microcompartment in the mitochondrial intermembrane space. The membrane-bound state of NDPK-D is favoured by the high affinity interaction with CL present in the inner mitochondrial membrane (marked in grey). This results in a functional interaction of NDPK-D with inner membrane ANT and allows for privileged exchange of metabolites and regulation of mitochondrial respiration. ATP exported by ANT is immediately transphosphorylated to GTP or other NTPs, while regenerated ADP is re-imported by ANT into the matrix space and used for ATP synthesis, thus functionally coupling the NDPK-D reaction to oxidative phosphorylation. The substrate and product fluxes related to the NDPK-D reaction are represented in red. The NDPK-D structure (PDB accession code 1EHW) is a surface charged representation (basic, blue and acid, red) described in [9]. (For interpretation of color in this figure the reader is referred to the web version of the article).

5. Conclusion Mitochondria are key organelles involved in cellular energy generation and programmed cell death. They exist in living cells as large tubular assemblies in close contact with nucleus, endoplasmic reticulum and microtubule networks [44]. Their structure is highly dynamic and can change (fusion and fission) depending on the bioenergetic state, cell cycle and apoptosis. Also, their ultrastructure, in particular that of cristae, is largely dependent on the bioenergetic state of the cell and/or the apoptotic stimuli. CL plays a central role for many mitochondrial functions. In the inner membrane, it glues the components of the respiratory chain supercomplexes. When transferred to the outer membrane upon apoptosis, it binds essential apoptosis-regulating factors. The mitochondrial kinases, NDPK-D and MtCK, which bind CL with high affinity, possess crucial properties that could control these processes. They can regulate mitochondrial ATP production by regenerating ADP within the mitochondrial intermembrane space, but they are also able to connect anionic phospholipid enriched membranes and to promote intermembrane phospholipid transfer [10,30]. Little is known about the factors that determine cristae structure. Mitochondrial dynamics requires specific GTPases involved in fusion such as DRP1 on the outer membrane or in fission such as OPA1 at the inner and mitofusins at the outer membrane [45]. In particular, OPA1 is required to maintain cristae structure and inner membrane integrity. Local generation of GTP by NDPK-D bound to the inner membrane could thus be involved in these processes. It should be noted that cristae remodelling is a vertebrate feature [46] and thus evolved together with the membrane association of NDPK-D. Finally, it should be mentioned that the equivalents of the surface NDPK-D basic motives, responsible for CL binding, are found on the cytosolic isoforms NDPK-A to -C but with a mixed acidic– basic character. This motif was involved in binding of cytosolic NDPK-B to phosphatidyl inositol in model liposomes and endoplasmic reticulum [47] and could also mediate the nucleotidedependent NDPK-A binding to membrane phospholipids recently reported [48]. Moreover, NDPK-B was shown to undergo, in vitro,

a GTP dependent self-assembly in ordered filaments [49]. These interactions could scaffold extended protein/protein and/or protein/lipid networks and modulate compartmentalized highenergy phosphate availability. Membrane association appears not limited to NDPK-D but could represent a more general property of NDPKs involved in their multi-faceted, not yet fully defined, functions within the cellular regulatory network. Acknowledgements We wish to thank Prof. T. Wallimann and Prof. I. Lascu for their continued interest in our work. We are indebted to Y. Chre´tien for assistance in figure preparation and to C. Mailleau for technical assistance. This work was supported by the Germaine de Stael program for Franco-Swiss collaboration (U.S.; M.L.L.), the Agence Nationale de la Recherche (chaire d’excellence to U.S.), the Marie Curie Intraeuropean Fellowship of the European Community (to M.T.-S.), the Institut National de la Sante´ et de la Recherche Me´dicale (INSERM) and grants (to M.L.L.) from the Groupement des Entreprises Françaises contre le Cancer (GEFLUC) and from the Association pour la Recherche contre le Cancer (ARC). References [1] [2] [3]

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