DNM1L

{{Short description|Protein-coding gene in humans}} {{Infobox_gene}} '''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.<ref name="pmid9348079">{{cite journal | vauthors = Shin HW, Shinotsuka C, Torii S, Murakami K, Nakayama K | title = Identification and subcellular localization of a novel mammalian dynamin-related protein homologous to yeast Vps1p and Dnm1p | journal = Journal of Biochemistry | volume = 122 | issue = 3 | pages = 525–30 | date = September 1997 | pmid = 9348079 | doi = 10.1093/oxfordjournals.jbchem.a021784 | doi-access = free }}</ref><ref name="pmid9731200">{{cite journal | vauthors = Hong YR, Chen CH, Cheng DS, Howng SL, Chow CC | title = Human dynamin-like protein interacts with the glycogen synthase kinase 3beta | journal = Biochemical and Biophysical Research Communications | volume = 249 | issue = 3 | pages = 697–703 | date = August 1998 | pmid = 9731200 | doi = 10.1006/bbrc.1998.9253 }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: DNM1L dynamin 1-like | url = https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=10059 }}</ref>

== 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.<ref name="pmid21102612">{{cite journal | vauthors = Westermann B | title = Mitochondrial fusion and fission in cell life and death | journal = Nature Reviews. Molecular Cell Biology | volume = 11 | issue = 12 | pages = 872–84 | date = December 2010 | pmid = 21102612 | doi = 10.1038/nrm3013 | s2cid = 3342603 }}</ref> There are 3 mouse and 6 human isoforms of Drp1, including a brain-specific variant.<ref name="pmid21145355">{{cite journal | vauthors = Reddy PH, Reddy TP, Manczak M, Calkins MJ, Shirendeb U, Mao P | title = Dynamin-related protein 1 and mitochondrial fragmentation in neurodegenerative diseases | journal = Brain Research Reviews | volume = 67 | issue = 1–2 | pages = 103–18 | date = June 2011 | pmid = 21145355 | pmc = 3061980 | doi = 10.1016/j.brainresrev.2010.11.004 }}</ref> Drp1 exists as homooligomers<ref>{{cite journal | vauthors = Kwapiszewska K, Kalwarczyk T, Michalska B, Szczepański K, Szymański J, Patalas-Krawczyk P, Andryszewski T, Iwan M, Duszyński J, Hołyst R | title = Determination of oligomerization state of Drp1 protein in living cells at nanomolar concentrations | journal = Scientific Reports | volume = 9 | issue = 1 | page = 5906 | date = April 2019 | pmid = 30976093 | doi = 10.1038/s41598-019-42418-0 | first8 = Bernadeta | first9 = Tomasz | first6 = Jędrzej | first7 = Krzysztof | pmc = 6459820 | bibcode = 2019NatSR...9.5906K }}</ref> and its function relies on its oligomerization ability.<ref>{{cite journal | vauthors = Michalska BM, Kwapiszewska K, Szczepanowska J, Kalwarczyk T, Patalas-Krawczyk P, Szczepański K, Hołyst R, Duszyński J, Szymański J | title = Insight into the fission mechanism by quantitative characterization of Drp1 protein distribution in the living cell | language = En | journal = Scientific Reports | volume = 8 | issue = 1 | page = 8122 | date = May 2018 | pmid = 29802333 | pmc = 5970238 | doi = 10.1038/s41598-018-26578-z | bibcode = 2018NatSR...8.8122M }}</ref>

== Function ==

Mitochondria routinely undergo fission and fusion events that maintain a dynamic reticular network. Drp1 is a fundamental component of mitochondrial fission.<ref>{{cite journal | vauthors = Smirnova E, Shurland DL, Ryazantsev SN, van der Bliek AM | title = A human dynamin-related protein controls the distribution of mitochondria | journal = The Journal of Cell Biology | volume = 143 | issue = 2 | pages = 351–8 | date = October 1998 | pmid = 9786947 | pmc = 2132828 | doi = 10.1083/jcb.143.2.351 }}</ref> Indeed, Drp1 deficient neurons have large, strongly interconnected mitochondria<ref name="pmid26777473">{{cite journal | vauthors = Wiemerslage L, Lee D | title = Quantification of mitochondrial morphology in neurites of dopaminergic neurons using multiple parameters | journal = Journal of Neuroscience Methods | volume = 262 | pages = 56–65 | date = March 2016 | pmid = 26777473 | pmc = 4775301 | doi = 10.1016/j.jneumeth.2016.01.008 }}</ref> 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.<ref name="ReferenceA">{{cite journal | vauthors = Archer SL | s2cid = 2346449 | title = Mitochondrial dynamics--mitochondrial fission and fusion in human diseases | journal = The New England Journal of Medicine | volume = 369 | issue = 23 | pages = 2236–51 | date = December 2013 | pmid = 24304053 | doi = 10.1056/NEJMra1215233 }}</ref> 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.<ref>{{cite journal | vauthors = Zhang C, Yuan XR, Li HY, Zhao ZJ, Liao YW, Wang XY, Su J, Sang SS, Liu Q | title = Downregualtion of dynamin-related protein 1 attenuates glutamate-induced excitotoxicity via regulating mitochondrial function in a calcium dependent manner in HT22 cells | journal = Biochemical and Biophysical Research Communications | volume = 443 | issue = 1 | pages = 138–43 | date = January 2014 | pmid = 24284040 | doi = 10.1016/j.bbrc.2013.11.072 }}</ref>

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.<ref name="pmid21145355"/>

In humans, loss of Drp1 function affects brain development and is also associated with early mortality.<ref name="pmid21102612"/>

== 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".<ref name="pmid21102612"/><ref>{{cite journal | vauthors = Lackner LL, Horner JS, Nunnari J | title = Mechanistic analysis of a dynamin effector | journal = Science | volume = 325 | issue = 5942 | pages = 874–7 | date = August 2009 | pmid = 19679814 | doi = 10.1126/science.1176921 | pmc = 6546417 | bibcode = 2009Sci...325..874L }}</ref> Drp1 has also been shown to interact with GSK3B.<ref name="pmid9731200"/> In mammals, Drp1 receptors include Mff, Mid49 and Mid51<ref>{{cite journal | vauthors = Otera H, Wang C, Cleland MM, Setoguchi K, Yokota S, Youle RJ, Mihara K | title = Mff is an essential factor for mitochondrial recruitment of Drp1 during mitochondrial fission in mammalian cells | journal = The Journal of Cell Biology | volume = 191 | issue = 6 | pages = 1141–58 | date = December 2010 | pmid = 21149567 | pmc = 3002033 | doi = 10.1083/jcb.201007152 }}</ref><ref>{{cite journal | vauthors = Palmer CS, Osellame LD, Laine D, Koutsopoulos OS, Frazier AE, Ryan MT | title = MiD49 and MiD51, new components of the mitochondrial fission machinery | journal = EMBO Reports | volume = 12 | issue = 6 | pages = 565–73 | date = June 2011 | pmid = 21508961 | pmc = 3128275 | doi = 10.1038/embor.2011.54 }}</ref>

Post-translational modifications to Drp1 (e.g. phosphorylation) can alter its activity and affect the rate of fission.<ref name="pmid18568013">{{cite journal | vauthors = Knott AB, Perkins G, Schwarzenbacher R, Bossy-Wetzel E | title = Mitochondrial fragmentation in neurodegeneration | journal = Nature Reviews. Neuroscience | volume = 9 | issue = 7 | pages = 505–18 | date = July 2008 | pmid = 18568013 | pmc = 2711514 | doi = 10.1038/nrn2417 }}</ref>

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.<ref>{{cite journal | vauthors = Xu S, Wang P, Zhang H, Gong G, Gutierrez Cortes N, Zhu W, Yoon Y, Tian R, Wang W | title = CaMKII induces permeability transition through Drp1 phosphorylation during chronic β-AR stimulation | journal = Nature Communications | volume = 7 | article-number = 13189 | date = October 2016 | pmid = 27739424 | pmc = 5067512 | doi = 10.1038/ncomms13189 | bibcode = 2016NatCo...713189X }}</ref> 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.<ref>{{cite journal | vauthors = Yan MH, Wang X, Zhu X | title = Mitochondrial defects and oxidative stress in Alzheimer disease and Parkinson disease | journal = Free Radical Biology & Medicine | volume = 62 | pages = 90–101 | date = September 2013 | pmid = 23200807 | pmc = 3744189 | doi = 10.1016/j.freeradbiomed.2012.11.014 }}</ref> 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.<ref>{{cite journal | vauthors = Guo X, Sesaki H, Qi X | title = Drp1 stabilizes p53 on the mitochondria to trigger necrosis under oxidative stress conditions in vitro and in vivo | journal = The Biochemical Journal | volume = 461 | issue = 1 | pages = 137–46 | date = July 2014 | pmid = 24758576 | pmc = 4381936 | doi = 10.1042/BJ20131438 }}</ref> 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.<ref name="ReferenceA"/>

== 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.<ref name="Bordt_2017">{{cite journal | vauthors = Bordt EA, Clerc P, Roelofs BA, Saladino AJ, Tretter L, Adam-Vizi V, Cherok E, Khalil A, Yadava N, Ge SX, Francis TC, Kennedy NW, Picton LK, Kumar T, Uppuluri S, Miller AM, Itoh K, Karbowski M, Sesaki H, Hill RB, Polster BM | title = The Putative Drp1 Inhibitor mdivi-1 Is a Reversible Mitochondrial Complex I Inhibitor that Modulates Reactive Oxygen Species | journal = Developmental Cell | volume = 40 | issue = 6 | pages = 583–594.e6 | date = March 2017 | pmid = 28350990 | pmc = 5398851 | doi = 10.1016/j.devcel.2017.02.020 }}</ref> The inhibitors putative function is preventing the GTPase activity of Drp1 thus preventing the activation and localization to the mitochondria.<ref name="ReferenceA"/> 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.<ref name="Sharp WW p1">{{cite journal | vauthors = Sharp WW, Fang YH, Han M, Zhang HJ, Hong Z, Banathy A, Morrow E, Ryan JJ, Archer SL | title = Dynamin-related protein 1 (Drp1)-mediated diastolic dysfunction in myocardial ischemia-reperfusion injury: therapeutic benefits of Drp1 inhibition to reduce mitochondrial fission | journal = FASEB Journal | volume = 28 | issue = 1 | pages = 316–26 | date = January 2014 | pmid = 24076965 | pmc = 3868827 | doi = 10.1096/fj.12-226225 | doi-access = free }}</ref> 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.<ref>{{cite journal | vauthors = Xie N, Wang C, Lian Y, Zhang H, Wu C, Zhang Q | title = A selective inhibitor of Drp1, mdivi-1, protects against cell death of hippocampal neurons in pilocarpine-induced seizures in rats | journal = Neuroscience Letters | volume = 545 | pages = 64–8 | date = June 2013 | pmid = 23628672 | doi = 10.1016/j.neulet.2013.04.026 | s2cid = 46558819 }}</ref> 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.<ref name="Sharp WW p1"/>

== References == {{reflist|33em}}

== Further reading == {{refbegin|33em}} * {{cite journal | vauthors = Pawlikowska P, Orzechowski A | title = [Role of transmembrane GTPases in mitochondrial morphology and activity] | journal = Postepy Biochemii | volume = 53 | issue = 1 | pages = 53–9 | year = 2007 | pmid = 17718388 }} * {{cite journal | vauthors = Kamimoto T, Nagai Y, Onogi H, Muro Y, Wakabayashi T, Hagiwara M | title = Dymple, a novel dynamin-like high molecular weight GTPase lacking a proline-rich carboxyl-terminal domain in mammalian cells | journal = The Journal of Biological Chemistry | volume = 273 | issue = 2 | pages = 1044–51 | date = January 1998 | pmid = 9422767 | doi = 10.1074/jbc.273.2.1044 | doi-access = free }} * {{cite journal | vauthors = Imoto M, Tachibana I, Urrutia R | title = Identification and functional characterization of a novel human protein highly related to the yeast dynamin-like GTPase Vps1p | journal = Journal of Cell Science | volume = 111 ( Pt 10) | issue = 10 | pages = 1341–9 | date = May 1998 | doi = 10.1242/jcs.111.10.1341 | pmid = 9570752 }} * {{cite journal | vauthors = Rasmussen RK, Rusak J, Price G, Robinson PJ, Simpson RJ, Dorow DS | title = Mixed-lineage kinase 2-SH3 domain binds dynamin and greatly enhances activation of GTPase by phospholipid | journal = The Biochemical Journal | volume = 335 ( Pt 1) | issue = Pt 1 | pages = 119–24 | date = October 1998 | pmid = 9742220 | pmc = 1219759 | doi = 10.1042/bj3350119 }} * {{cite journal | vauthors = Smirnova E, Shurland DL, Ryazantsev SN, van der Bliek AM | title = A human dynamin-related protein controls the distribution of mitochondria | journal = The Journal of Cell Biology | volume = 143 | issue = 2 | pages = 351–8 | date = October 1998 | pmid = 9786947 | pmc = 2132828 | doi = 10.1083/jcb.143.2.351 }} * {{cite journal | vauthors = Smirnova E, Griparic L, Shurland DL, van der Bliek AM | title = Dynamin-related protein Drp1 is required for mitochondrial division in mammalian cells | journal = Molecular Biology of the Cell | volume = 12 | issue = 8 | pages = 2245–56 | date = August 2001 | pmid = 11514614 | pmc = 58592 | doi = 10.1091/mbc.12.8.2245 }} * {{cite journal | vauthors = Karbowski M, Lee YJ, Gaume B, Jeong SY, Frank S, Nechushtan A, Santel A, Fuller M, Smith CL, Youle RJ | title = Spatial and temporal association of Bax with mitochondrial fission sites, Drp1, and Mfn2 during apoptosis | journal = The Journal of Cell Biology | volume = 159 | issue = 6 | pages = 931–8 | date = December 2002 | pmid = 12499352 | pmc = 2173996 | doi = 10.1083/jcb.200209124 }} * {{cite journal | vauthors = Koch A, Thiemann M, Grabenbauer M, Yoon Y, McNiven MA, Schrader M | title = Dynamin-like protein 1 is involved in peroxisomal fission | journal = The Journal of Biological Chemistry | volume = 278 | issue = 10 | pages = 8597–605 | date = March 2003 | pmid = 12499366 | doi = 10.1074/jbc.M211761200 | doi-access = free }} * {{cite journal | vauthors = Li X, Gould SJ | title = The dynamin-like GTPase DLP1 is essential for peroxisome division and is recruited to peroxisomes in part by PEX11 | journal = The Journal of Biological Chemistry | volume = 278 | issue = 19 | pages = 17012–20 | date = May 2003 | pmid = 12618434 | doi = 10.1074/jbc.M212031200 | doi-access = free }} * {{cite journal | vauthors = Breckenridge DG, Stojanovic M, Marcellus RC, Shore GC | title = Caspase cleavage product of BAP31 induces mitochondrial fission through endoplasmic reticulum calcium signals, enhancing cytochrome c release to the cytosol | journal = The Journal of Cell Biology | volume = 160 | issue = 7 | pages = 1115–27 | date = March 2003 | pmid = 12668660 | pmc = 2172754 | doi = 10.1083/jcb.200212059 }} * {{cite journal | vauthors = Yoon Y, Krueger EW, Oswald BJ, McNiven MA | title = The mitochondrial protein hFis1 regulates mitochondrial fission in mammalian cells through an interaction with the dynamin-like protein DLP1 | journal = Molecular and Cellular Biology | volume = 23 | issue = 15 | pages = 5409–20 | date = August 2003 | pmid = 12861026 | pmc = 165727 | doi = 10.1128/MCB.23.15.5409-5420.2003 }} * {{cite journal | vauthors = Howng SL, Sy WD, Cheng TS, Lieu AS, Wang C, Tzou WS, Cho CL, Hong YR | title = Genomic organization, alternative splicing, and promoter analysis of human dynamin-like protein gene | journal = Biochemical and Biophysical Research Communications | volume = 314 | issue = 3 | pages = 766–72 | date = February 2004 | pmid = 14741701 | doi = 10.1016/j.bbrc.2003.12.172 }} * {{cite journal | vauthors = Lee YJ, Jeong SY, Karbowski M, Smith CL, Youle RJ | title = Roles of the mammalian mitochondrial fission and fusion mediators Fis1, Drp1, and Opa1 in apoptosis | journal = Molecular Biology of the Cell | volume = 15 | issue = 11 | pages = 5001–11 | date = November 2004 | pmid = 15356267 | pmc = 524759 | doi = 10.1091/mbc.E04-04-0294 }} * {{cite journal | vauthors = Pitts KR, McNiven MA, Yoon Y | title = Mitochondria-specific function of the dynamin family protein DLP1 is mediated by its C-terminal domains | journal = The Journal of Biological Chemistry | volume = 279 | issue = 48 | pages = 50286–94 | date = November 2004 | pmid = 15364948 | doi = 10.1074/jbc.M405531200 | doi-access = free }} * {{cite journal |author23-link=Bernhard Landwehrmeyer| vauthors = Goehler H, Lalowski M, Stelzl U, Waelter S, Stroedicke M, Worm U, Droege A, Lindenberg KS, Knoblich M, Haenig C, Herbst M, Suopanki J, Scherzinger E, Abraham C, Bauer B, Hasenbank R, Fritzsche A, Ludewig AH, Büssow K, Buessow K, Coleman SH, Gutekunst CA, Landwehrmeyer BG, Lehrach H, Wanker EE | title = A protein interaction network links GIT1, an enhancer of huntingtin aggregation, to Huntington's disease | journal = Molecular Cell | volume = 15 | issue = 6 | pages = 853–65 | date = September 2004 | pmid = 15383276 | doi = 10.1016/j.molcel.2004.09.016 | doi-access = free }} * {{cite journal | vauthors = Germain M, Mathai JP, McBride HM, Shore GC | title = Endoplasmic reticulum BIK initiates DRP1-regulated remodelling of mitochondrial cristae during apoptosis | journal = The EMBO Journal | volume = 24 | issue = 8 | pages = 1546–56 | date = April 2005 | pmid = 15791210 | pmc = 1142564 | doi = 10.1038/sj.emboj.7600592 }} * {{cite journal | vauthors = Narayanan R, Leonard M, Song BD, Schmid SL, Ramaswami M | title = An internal GAP domain negatively regulates presynaptic dynamin in vivo: a two-step model for dynamin function | journal = The Journal of Cell Biology | volume = 169 | issue = 1 | pages = 117–26 | date = April 2005 | pmid = 15824135 | pmc = 2171915 | doi = 10.1083/jcb.200502042 }} {{refend}}

== External links == * {{UCSC genome browser|DNM1L}} * {{UCSC gene details|DNM1L}} * {{PDBe-KB2|O00429|Dynamin-1-like protein}}