Figure 1

(a) Genetic interaction between NM23 and dynamin homologs in Drosophila. Left: a mutant of the dynamin homolog in Drosophila (shibire), which is temperature sensitive, present no paralysis at a permissive temperature, 19 °C. Middle: the shibire mutant present paralysis of the flies due to defects in endocytosis-mediated neurotransmitter uptake at a non-permissive temperature, 29 °C. Right: combination of mutations of awd, the homolog of NM23-H1/-H2 in Drosophila, and mutations of shibire induces paralysis at a lower temperature 22 °C, indicating that mutations of NM23 make synapses more sensitive to dynamin mutations. (b) Genetic interaction between NM23 and dynamin homologs in C. elegans. In order to test whether NDPK/NDK-1 and DYN-1/Dynamin also interact in the worm genetically, ndk-1−/−;dyn-1−/− double mutants were generated. The viable thermosensitive ky51 allele of dyn-1 (dyn-1−/−) results in 50% embryonic lethality at the restrictive temperature (25 °C). These embryos arrest development at a late embryonic stage due to endocytosis defects and display an accumulation of cell corpses. In the progeny of ndk-1+/− heterozygotes 16% of ndk-1−/−;dyn-1−/−homozygotes die as embryos showing the Dyn-1-like late embryonic lethality phenotype with persistent cell corpses. Double mutants at the restrictive temperature resulted in no viable progeny (100% embryonic lethality). (c) NM23-H1 a GTP dealer for dynamin at clathrin-coated pits during endocytosis. Dynamin is recruited at the plasma membrane clathrin-coated pits, polymerizes into helix which strongly stimulates its GTPase activity inducing GTP hydrolysis; multiple cycles of GTP loading and hydrolysis are necessary for constriction and fission. To load very efficiently and locally the GTP on dynamin, NM23-H1 physically interacts with dynamin at clathrin-coated pits and uses the GDP coming from the GTP hydrolysis and the cytosolic ATP pool to produce GTP in a closed circuit. Finally, to increase the efficiency of the reaction, a hexamer of NM23-H1 interacts with dynamin, this hexamer containing six active sites that can function in concert, ensuring in a same time six catalytic reactions. (d) NM23-H4 controls mitochondrial fusion through a functional coupling with the dynamin-related GTPase OPA1. A hexamer of NM23-H4 binding to the mitochondrial inner membrane harbors NDPK activity for regeneration of NTP, mainly GTP, in the mitochondrial intermembrane space, and for direct and local GTP fueling (channeling-tunneling) of the dynamin-related protein OPA1. NM23-H4 also channels ADP via adenylate translocase (ANT) into the matrix space for stimulation of respiration and ATP regeneration through oxidative phosphorylation (OXPHOS). The localization of NM23-H3 at the mitochondrial surface where the dynamin-related pro-fission protein Drp1 acts could suggest that the NDPK NM23-H3 could assist Drp1 by GTP fueling during mitochondrial fission. MOM, mitochondrial outer membrane; IMS, intermembrane space; MIM, mitochondrial inner membrane; ANT, adenylate translocase; OXPHOS, oxidative phosphorylation. (e) NM23-H1 controls dynamin-mediated endocytosis. Left: NM23-H1 facilitates clathrin-dependent and dynamin-dependent internalization of E-cadherin, transferrin receptor (TfR), epidermal growth factor receptor (EGFR), fibroblast growth factor (FGFR), and platelet-derived growth factor receptor (PDGFR). Right: NM23-H1 facilitates clathrin- and caveolin-independent and dynamin-dependent internalization of the β subunit of the interleukin 2 receptor (IL2Rβ).