Mitochondria continually change shape through the combined actions of fission, fusion, and movement along cytoskeletal tracks. The lengths of mitochondria and the degree to which they form closed networks are determined by the balance between fission and fusion rates. These rates are influenced by metabolic and pathogenic conditions inside mitochondria and by their cellular environment. Fission and fusion are important for growth, for mitochondrial redistribution, and for maintenance of a healthy mitochondrial network. In addition, mitochondrial fission and fusion play prominent roles in disease-related processes such as apoptosis and mitophagy. Three members of the Dynamin family are key components of the fission and fusion machineries. Their functions are controlled by different sets of adaptor proteins on the surface of mitochondria and by a range of regulatory processes. Here, we review what is known about these proteins and the processes that regulate their actions.

Dynamin superfamily molecular motors use guanosine triphosphate (GTP) as a source of energy for membrane-remodeling events. We found that knockdown of nucleoside diphosphate kinases (NDPKs) NM23-H1/H2, which produce GTP through adenosine triphosphate (ATP)-driven conversion of guanosine diphosphate (GDP), inhibited dynamin-mediated endocytosis. NM23-H1/H2 localized at clathrin-coated pits and interacted with the proline-rich domain of dynamin. In vitro, NM23-H1/H2 were recruited to dynamin-induced tubules, stimulated GTP-loading on dynamin, and triggered fission in the presence of ATP and GDP. NM23-H4, a mitochondriaspecific NDPK, colocalized with mitochondrial dynamin-like OPA1 involved in mitochondria * Corresponding author. mathieu.boissan@inserm.fr (M.B.); philippe.chavrier@curie.fr (P.C. Europe PMC Funders Author ManuscriptsEurope PMC Funders Author Manuscripts inner membrane fusion and increased GTP-loading on OPA1. Like OPA1 loss of function, silencing of NM23-H4 but not NM23-H1/H2 resulted in mitochondrial fragmentation, reflecting fusion defects. Thus, NDPKs interact with and provide GTP to dynamins, allowing these motor proteins to work with high thermodynamic efficiency.The 100-kD dynamin guanosine triphosphatase (GTPase) promotes uptake of cell-surface receptors both by clathrin-dependent and -independent pathways (1, 2). Dynamin polymerizes into helix around the neck of endocytic pits and induces guanosine triphosphate (GTP) hydrolysis-driven membrane fission (3-7). Typical of molecular motors, dynamin has a low affinity for GTP and a high basal GTP-hydrolysis rate, which can be further stimulated by dynamin polymerization (8,9). This maximizes chemical energy gain and kinetics of hydrolysis, respectively, which in vivo depend on high concentration ratios of adenosine triphosphate/adenosine diphosphate (ATP/ADP) or GTP/guanosine diphosphate (GDP). The cellular concentrations of GTP and GDP are at least a factor of 10 lower than those of ATP and ADP, and GTP/GDP ratios could thus decrease much more rapidly at elevated workload, both of which make GTP not an ideal substrate for high-turnover, energy-dependent enzymes. Paradoxically, dynamin GTPases are among the most powerful molecular motors described (7).Studies in Drosophila identified a genetic interaction between dynamin and Awd (10-12). Awd belongs to the family of nucleoside diphosphate kinases (NDPKs), which catalyze synthesis of nucleoside triphosphates, including GTP, from corresponding nucleoside diphosphates and ATP (13). The most abundant human NDPKs are the highly related cytosolic proteins NM23-H1 and -H2. NM23-H4, another NDPK-family member, localizes exclusively at the mitochondrial inner membrane (14, 15). Mitochondrial membrane dynamics require dynamin-related GTPases (16). We hypothesized that NDPKs could influence the function of dynamin family members in membrane-remodeling events through spatially controlled GTP production and availability.Knockdown of NM23-H1 and -H2 (fig. S1, A to E) reduced clathrin-dependent endocyt...

The mitochondrial fission protein Drp1 binds to Mff on mitochondria, followed by entry into a complex with Fis1 at the ER–mitochondrial interface. Mutations in Fis1 disrupt disposal of defective mitochondria when fission is induced by stress. Fis1 thus acts in sequence with Mff to couple mitochondrial fission with downstream degradation processes.

Arginine methylation of histone and non-histone proteins is involved in transcription regulation and many other cellular processes. Nevertheless, whether such protein modification plays a regulatory role during apoptosis remains largely unknown. Here we report that the Caenorhabditis elegans homolog of mammalian type II arginine methyltransferase PRMT5 negatively regulates DNA damage-induced apoptosis. We show that inactivation of C. elegans prmt-5 leads to excessive apoptosis in germline following ionizing irradiation, which is due to a CEP-1/p53–dependent up-regulation of the cell death initiator EGL-1. Moreover, we provide evidence that CBP-1, the worm ortholog of human p300/CBP, functions as a cofactor of CEP-1. PRMT-5 forms a complex with both CEP-1 and CBP-1 and can methylate the latter. Importantly, down-regulation of cbp-1 significantly suppresses DNA damage-induced egl-1 expression and apoptosis in prmt-5 mutant worms. These findings suggest that PRMT-5 likely represses CEP-1 transcriptional activity through CBP-1, which represents a novel regulatory mechanism of p53-dependent apoptosis.