Disease relevance of DNM1L

• Nuclear gene OPA1, encoding a mitochondrial dynamin-related protein, is mutated in dominant optic atrophy [1].
• A clue that these new findings are of significance for the pathogenesis of neurodegenerative disease is provided by the observation that OPA-1, a dynamin-related GTPase regulating mitochondrial fusion, is mutated in humans with dominant optic atrophy, which is characterized by degeneration of retinal ganglion cells and childhood blindness [2].
• We have recently shown, with others, that mutations in the OPA1 gene encoding a dynamin-related mitochondrial protein, underlie the dominant form of optic atrophy [3].
• In particular, one of the HdynIV variant overexpressions has been suggested to contribute to the pathogenesis of brain tumors [4].

High impact information on DNM1L

• (2006) show that a rhomboid intramembrane protease PARL and a dynamin-related protein OPA1 are critical regulators of cristae remodeling [5].
• Here, we show that the conserved intermembrane-space dynamin-related GTPase Mgm1 is required to tether and fuse mitochondrial inner membranes [6].
• Outer-membrane fusion requires trans interactions of the dynamin-related GTPase Fzo1, GTP hydrolysis, and an intact inner-membrane proton gradient [6].
• Mitochondrial Inner-Membrane Fusion and Crista Maintenance Requires the Dynamin-Related GTPase Mgm1 [6].
• OPA1, encoding a dynamin-related GTPase, is mutated in autosomal dominant optic atrophy linked to chromosome 3q28 [7].

Biological context of DNM1L

• Roles of the mammalian mitochondrial fission and fusion mediators Fis1, Drp1, and Opa1 in apoptosis [8].
• Down-regulation of hFis1 powerfully inhibits cell death to an extent significantly greater than down-regulation of Drp1 and at a stage of apoptosis distinct from that induced by Drp1 inhibition [8].
• We have recently identified a novel and conserved mitochondrial rhomboid intramembrane protease that controls membrane fusion in Saccharomyces cerevisiae by processing the dynamin-like GTPase, Mgm1, thereby releasing it from the membrane [9].
• To study how mitochondria dynamics affects cell Ca2+ homeostasis, we overexpressed two mitochondrial fission proteins, hFis1 and Drp1, and measured Ca2+ changes within the cytosol and the ER in HeLa cells [10].
• It was further established that there are three patterns of alternative splicing producing in-frame deletions in the coding sequence of dymple in a tissue-specific manner [11].

Anatomical context of DNM1L

• Adenoviral expression of p20 caused an early release of Ca2+ from the ER, concomitant uptake of Ca2+ into mitochondria, and mitochondrial recruitment of Drp1, a dynamin-related protein that mediates scission of the outer mitochondrial membrane, resulting in dramatic fragmentation and fission of the mitochondrial network [12].
• We describe here a nuclear gene, OPA1, that maps within the candidate region and encodes a dynamin-related protein localized to mitochondria [1].
• Dynamins are large GTPases that belong to a protein superfamily that, in eukaryotic cells, includes classical dynamins, dynamin-like proteins, OPA1, Mx proteins, mitofusins and guanylate-binding proteins/atlastins [13].
• The morphology of other organelles was unaffected by mutant Drp1 [14].
• The endoplasmic reticulum (ER) can elicit proapoptotic signalling that results in transmission of Ca(2+) to the mitochondria, which in turn stimulates recruitment of the fission enzyme DRP1 to the surface of the organelle [15].

Associations of DNM1L with chemical compounds

• When the full-length cDNA of HdynIV was sequenced, it showed that HdynIV's carboxyl terminal lacks a proline-rich domain that can bind to Gsk-3 beta [16].
• Nitric oxide-induced mitochondrial fission is regulated by dynamin-related GTPases in neurons [17].
• Consequently, in Drp-1-expressing cells the apoptotic efficacy of ceramide, which causes a Ca2+-dependent perturbation of mitochondrial structure and function, was drastically reduced [18].
• DRP-1/Ku DNA binding was assessed in mobility shift assays and competition binding assays using cisplatin-damaged DNA [19].
• This could be a dynamin-like GTP-ase, since GTP gamma S-stimulated tubule formation has only been reported previously in cases where a dynamin is involved [20].
• We have identified cAMP-dependent protein kinase-dependent phosphorylation of Drp1 within the GED domain at Ser(637) that inhibits Drp1 GTPase activity [21].
• Drp1 phosphorylation at Ser 656 provides a mechanism for the integration of cAMP and calcium signals in the control of mitochondrial shape, apoptosis and other aspects of mitochondrial function [22].

Physical interactions of DNM1L

• In the present report, we have demonstrated that HdynIV interacts with the Gsk-3 beta through its carboxyl-terminal region, implying than HdynIV may also be involved in cell signaling [16].
• Human dynamin-like protein interacts with the glycogen synthase kinase 3beta [16].
• To investigate its function, we searched for PKP3-interacting proteins and identified dynamin 1-like, which was also activated in NSCLC [23].

Other interactions of DNM1L

• The yeast protein Fis1p has been shown to participate in mitochondrial fission mediated by the dynamin-related protein Dnm1p [24].
• We have screened about 16,000 small molecules and have identified 1, named here dynasore, that interferes in vitro with the GTPase activity of dynamin1, dynamin2, and Drp1, the mitochondrial dynamin, but not of other small GTPases [25].
• Co-transfection of DLP1 siRNA with Pex11pbeta, a peroxisomal membrane protein involved in peroxisome proliferation, induced further elongation and network formation of the peroxisomal compartment [26].
• Together, these findings indicate that yeast and mammalian cells have a conserved programmed death pathway regulated by a common molecular component, Drp1/Dnm1, that is inhibited by a Bcl-2-like function [27].
• Misregulated interaction between DLP1 and hFis1 by alpha1 deletion induced mitochondrial swelling, in part by the mitochondrial permeability transition, but significantly delayed cell death [28].

Analytical, diagnostic and therapeutic context of DNM1L

• By Northern blot analysis and isoform-specific PCR, we found that HdynIV is expressed ubiquitously in all human tissues examined [16].
• Immunofluorescence and subcellular fractionation show that endogenous Drp1 is localized to mitochondria, which is also consistent with a role in mitochondrial division [29].
• They further indicate that peroxisomal elongation, constriction and fission require distinct sets of proteins, and that the dynamin-like protein DLP1 functions primarily in the latter process [26].
• Northern blot analysis reveals that the DRP1 mRNA is detected at high levels in human muscle, heart, kidney and brain [30].
• Immunolocalization studies in Chinese hamster ovary (CHO) cells using an epitope-tagged form of DRP1 and confocal microscopy show that this protein is concentrated in a perinuclear region that labels with the endoplasmic reticulum marker DiOC6(3) and the Golgi marker C5-DMB-Cer [30].

References