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.