Abstract
Peroxisomes proliferate by sequential processes comprising elongation, constriction, and scission of peroxisomal membrane. It is known that the constriction step is mediated by a GTPase named dynamin-like protein 1 (DLP1) upon efficient loading of GTP. However, mechanism of fuelling GTP to DLP1 remains unknown in mammals. We earlier show that nucleoside diphosphate (NDP) kinase-like protein, termed dynamin-based ring motive-force organizer 1 (DYNAMO1), generates GTP for DLP1 in a red alga, Cyanidioschyzon merolae. In the present study, we identified that nucleoside diphosphate kinase 3 (NME3), a mammalian homologue of DYNAMO1, localizes to peroxisomes. Elongated peroxisomes were observed in cells with suppressed expression of NME3 and fibroblasts from a patient lacking NME3 due to the homozygous mutation at the initiation codon of NME3. Peroxisomes proliferated by elevation of NME3 upon silencing the expression of ATPase family AAA domain containing 1, ATAD1. In the wild-type cells expressing catalytically-inactive NME3, peroxisomes were elongated. These results suggest that NME3 plays an important role in peroxisome division in a manner dependent on its NDP kinase activity. Moreover, the impairment of peroxisome division reduces the level of ether-linked glycerophospholipids, ethanolamine plasmalogens, implying the physiological importance of regulation of peroxisome morphology.
Highlights
Peroxisomes proliferate by division involving elongation, constriction, and fission [1,2,3]
Silencing of NME3 expression in HeLa cells causes the elongation of peroxisomes, which is observed in the fibroblasts from NME3-deficient patient devoid of the expression of NME3
Our morphological results showing the elongated peroxisomes in HeLa cells silenced in the NME3 expression and the nme3 patient’s fibroblasts suggest that NME3 more likely provides GTP to GTPases required for fission of peroxisomes
Summary
Peroxisomes proliferate by division involving elongation, constriction, and fission [1,2,3]. Peroxisome division is mediated by several factors including Pex11β, dynamin-like protein 1 (DLP1) [4,5], mitochondrial fission factor (Mff) [6,7], and Fission 1 (Fis1) [8,9] in mammals [10]. Except for Pex11β, these proteins are originally identified as fission factors of mitochondria, indicating that peroxisomes share a common division-machinery with mitochondria [2,8,11]. N-terminal amphipathic helix region of Pex11β is required for the formation of Pex11β homo-oligomer and interaction with membrane phospholipids, leading to deformation of peroxisomal membrane [15,16,17]. Docosahexaenoic acid, a poly-unsaturated fatty acid of peroxisomal β-oxidation metabolites, induces elongation of peroxisomes, hyper-oligomerization of Pex11β on the elongated regions, and extension of Pex11β-enriched membrane [7]
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