DNM1L

DNM1L
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 3W6N, 3W6O, 3W6P, 4BEJ, 4H1U, 4H1V
Identifiers
Aliases	DNM1L, DLP1, DRP1, DVLP, DYMPLE, EMPF, HDYNIV, dynamin 1-like, dynamin 1 like, EMPF1, OPA5
External IDs	OMIM: 603850; MGI: 1921256; HomoloGene: 6384; GeneCards: DNM1L; OMA:DNM1L - orthologs
Gene location (Human) Chr. Chromosome 12 (human)[1] Band 12p11.21 Start 32,679,200 bp[1] End 32,745,650 bp[1]
Gene location (Mouse) Chr. Chromosome 16 (mouse)[2] Band 16|16 A2 Start 16,130,094 bp[2] End 16,176,823 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in lateral nuclear group of thalamus Pars compacta sperm pars reticulata Brodmann area 23 external globus pallidus parietal lobe superior vestibular nucleus postcentral gyrus entorhinal cortex Top expressed in ventral tegmental area dorsomedial hypothalamic nucleus habenula dorsal tegmental nucleus pontine nuclei medial geniculate nucleus lateral hypothalamus paraventricular nucleus of hypothalamus lateral geniculate nucleus medial dorsal nucleus More reference expression data BioGPS More reference expression data
Gene ontology Molecular function nucleotide binding protein homodimerization activity GTP binding protein binding GTPase activity identical protein binding hydrolase activity ubiquitin protein ligase binding lipid binding GTPase activator activity GTP-dependent protein binding microtubule binding clathrin binding protein-containing complex binding BH2 domain binding Cellular component cytoplasm cytosol Golgi apparatus membrane intracellular membrane-bounded organelle microtubule cytoskeleton peroxisome synapse synaptic vesicle membrane mitochondrial outer membrane cell junction mitochondrion brush border perinuclear region of cytoplasm clathrin-coated pit microtubule cytoplasmic vesicle endomembrane system endoplasmic reticulum membrane Golgi membrane endoplasmic reticulum mitochondrial membranes protein-containing complex postsynapse presynaptic endocytic zone membrane mitochondrion-derived vesicle secretory vesicle Biological process mitochondrial fragmentation involved in apoptotic process regulation of ATP metabolic process positive regulation of mitochondrial fission endocytosis cellular component disassembly involved in execution phase of apoptosis mitochondrial fission regulation of mitochondrion organization regulation of protein oligomerization regulation of peroxisome organization membrane fusion peroxisome fission regulation of autophagy of mitochondrion positive regulation of protein secretion positive regulation of apoptotic process protein localization to mitochondrion positive regulation of release of cytochrome c from mitochondria necroptosis dynamin family protein polymerization involved in mitochondrial fission heart contraction mitochondrion morphogenesis protein homotetramerization mitochondrial membrane fission positive regulation of intrinsic apoptotic signaling pathway release of cytochrome c from mitochondria positive regulation of GTPase activity protein complex oligomerization programmed cell death mitochondrion organization endoplasmic reticulum organization apoptotic mitochondrial changes negative regulation of mitochondrial fusion synaptic vesicle recycling via endosome intracellular distribution of mitochondria synaptic vesicle endocytosis protein homooligomerization positive regulation of dendritic spine morphogenesis cellular response to lipid cellular response to oxygen-glucose deprivation execution phase of apoptosis positive regulation of synaptic vesicle endocytosis response to flavonoid response to hypobaric hypoxia positive regulation of synaptic vesicle exocytosis calcium ion transport regulation of gene expression regulation of ubiquitin protein ligase activity rhythmic process Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 10059 74006 Ensembl ENSG00000087470 ENSMUSG00000022789 UniProt O00429 Q8K1M6 RefSeq (mRNA) NM_001278463 NM_001278464 NM_001278465 NM_001278466 NM_005690 NM_012062 NM_012063 NM_001330380 NM_001025947 NM_001276340 NM_001276341 NM_152816 NM_001360007 NM_001360008 NM_001360009 NM_001360010 RefSeq (protein) NP_001265392 NP_001265393 NP_001265394 NP_001265395 NP_001317309 NP_005681 NP_036192 NP_036193 NP_001021118 NP_001263269 NP_001263270 NP_690029 NP_001346936 NP_001346937 NP_001346938 NP_001346939 NP_001392181 NP_001392182 NP_001392183 NP_001392184 NP_001392185 NP_001392186 NP_001392187 NP_001392188 NP_001392189 NP_001392190 NP_001392191 NP_001392192 NP_001392193 NP_001392194 Location (UCSC) Chr 12: 32.68 – 32.75 Mb Chr 16: 16.13 – 16.18 Mb PubMed search [3] [4]
Wikidata
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Dynamin-1-like protein is a GTPase that regulates mitochondrial fission. In humans, dynamin-1-like protein, which is typically referred to as dynamin-related protein 1 (Drp1), is encoded by the DNM1L gene and is part of the dynamin superfamily (DSP) family of proteins.^[5][6][7]

Structure

Drp1, which is a member of the dynamin superfamily of proteins, consists of a GTPase and GTPase effector domain that are separated from each other by a helical segment of amino acids.^[8] There are 3 mouse and 6 human isoforms of Drp1, including a brain-specific variant.^[9] Drp1 exists as homooligomers^[10] and its function relies on its oligomerization ability.^[11]

Function

Mitochondria routinely undergo fission and fusion events that maintain a dynamic reticular network. Drp1 is a fundamental component of mitochondrial fission.^[12] Indeed, Drp1 deficient neurons have large, strongly interconnected mitochondria^[13] due to dysfunctional fission machinery. Fission helps facilitate mitophagy, which is the breakdown and recycling of damaged mitochondria. Dysfunction in the DRP activity may result in mutated DNA or malfunctioning proteins diffusing throughout the mitochondrial system. In addition, fission results in fragmented mitochondria more capable of producing of reactive oxygen species, which can disrupt normal biochemical processes inside of cells.^[14] ROS can be formed from incomplete transfer of electrons through the electron transport chain. Furthermore, fission influences calcium flux within the cell, linking Drp1 to apoptosis and cancer.^[15]

Several studies have indicated that Drp1 is essential for proper embryonic development. Drp1 knockout mice exhibit abnormal brain development and die around embryonic day 12. In neural specific Drp1 knockout mice, brain size is reduced and apoptosis is increased. Synapse formation and neurite growth are also impaired. A second group of researchers generated another neural specific knockout mouse line. They found that knocking out Drp1 resulted in the appearance of large mitochondria in Purkinje cells and prevented neural tube formation.^[9]

In humans, loss of Drp1 function affects brain development and is also associated with early mortality.^[8]

Interactions

The majority of knowledge about mitochondrial fission comes from studies with yeast. The yeast homolog of Drp1 is dynamin-1 (Dnm1), which interacts with Fis1 through Mdv1. This interaction causes Dnm1 to oligomerize and form rings around dividing mitochondria at the so-called "constriction point".^[8][16] Drp1 has also been shown to interact with GSK3B.^[6] In mammals, Drp1 receptors include Mff, Mid49 and Mid51^[17][18]

Post-translational modifications to Drp1 (e.g. phosphorylation) can alter its activity and affect the rate of fission.^[19]

Drp1 has two major phosphorylation sites. The CDK phosphorylation site is S579, and the PKA site is S600 in Drp1 isoform 3. Phosphorylation by CDK is thought to be activating, whereas PKA phosphorylation is thought to be inhibitory. Recently, CaMKII was shown to phosphorylate Drp1 at S616. This was shown to occur in response to chronic Beta-adrenergic stimulation and to promote mPTP opening.^[20] Other post-translational modifications include S-nitrosylation, sumoylation, and ubiquitination. Higher S- nitrosylation modifications of Drp1, which enhances Drp1 activity, have been observed in Alzheimer’s Disease. Furthermore, Drp1 has been shown to interact with Aβ monomers, thought to play an important role in Alzheimer’s Disease, exacerbating the disease and its symptoms.^[21] Drp1 has been linked to a number of pathways and processes including cell division, apoptosis, and necrosis. Drp1 has been shown to stabilize p53 during oxidative stress, promoting its translocation to the mitochondria and encouraging mitochondrial- related necrosis.^[22] In addition, cyclin B1- CDK activates Drp1, causing fragmentation and ensuring mitochondria are distributed to each daughter cell after mitosis. Likewise, different transcriptional controllers are able to alter Drp1 activity through gene expression and regulation. For example, PPARGC1A and [HIF1A] regulated Drp1 activity through gene expression.^[14]

Therapy

Inhibition of Drp1 has been considered for possible therapeutics for a variety of diseases. The most studied inhibitor is a small molecule named mitochondrial division inhibitor 1 (mdivi-1) which may have off-target effects such as inhibition of complex 1 of the mitochondrial respiratory chain.^[23] The inhibitors putative function is preventing the GTPase activity of Drp1 thus preventing the activation and localization to the mitochondria.^[14] Midiv-1 has been demonstrated to attenuate the effects of ischemia reperfusion injury after cardiac arrest. The treatment prevented both mitochondria fragmentation and increased cell viability.^[24] Similarly, midiv-1 has demonstrated neuroprotective effects by greatly reducing neuron death due to seizure. Furthermore, the study showed midiv-1 was capable to preventing the activation of caspase 3 by reversing the release of cytochrome c in intrinsic apoptosis.^[25] Whether mdivi-1 inhibits Drp1 or not, its therapeutic potential is certainly evident. Other than directly inhibiting Drp1, certain inhibitors of proteins involved in the posttranslational modifications of Drp1 have been studied. FK506 is a calcineurin inhibitor, which functions to dephosphorylate the serine 637 position of Drp1, encouraging translocation to the mitochondria and fragmentation. FK506 was shown to also preserve mitochondrial morphology after reperfusion injury.^[24]

References

Further reading

External links

• DNM1L human gene location in the UCSC Genome Browser.
• DNM1L human gene details in the UCSC Genome Browser.
• Overview of all the structural information available in the PDB for UniProt: O00429 (Dynamin-1-like protein) at the PDBe-KB.