{{Short description|Protein-coding gene in the species Homo sapiens}} {{Infobox_gene}} '''Mitochondrial Rho GTPase 1''' (MIRO1) is an [[enzyme]] that in humans is encoded by the ''RHOT1'' [[gene]] on chromosome 17.<ref name="pmid12482879">{{cite journal | vauthors = Fransson A, Ruusala A, Aspenström P | title = Atypical Rho GTPases have roles in mitochondrial homeostasis and apoptosis | journal = The Journal of Biological Chemistry | volume = 278 | issue = 8 | pages = 6495–502 | date = Feb 2003 | pmid = 12482879 | doi = 10.1074/jbc.M208609200 | doi-access = free }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: RHOT1 ras homolog gene family, member T1| url = https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=55288}}</ref> As a [[Miro (protein)|Miro]] protein [[isoform]], the protein facilitates mitochondrial transport by attaching the [[mitochondria]] to the motor/adaptor complex.<ref name="pmid23732472">{{cite journal | vauthors = Schwarz TL | title = Mitochondrial trafficking in neurons | journal = Cold Spring Harbor Perspectives in Biology | volume = 5 | issue = 6 | date = Jun 2013 | pmid = 23732472 | doi = 10.1101/cshperspect.a011304 | article-number=a011304 | pmc=3660831}}</ref> Through its key role in mitochondrial transport, RHOT1 is involved in mitochondrial [[homeostasis]] and [[apoptosis]], as well as [[Parkinson's disease]] (PD) and [[cancer]].<ref name="pmid23732472"/><ref name="pmid25761903">{{cite journal | vauthors = van der Merwe C, Jalali Sefid Dashti Z, Christoffels A, Loos B, Bardien S | title = Evidence for a common biological pathway linking three Parkinson's disease-causing genes: parkin, PINK1 and DJ-1 | journal = The European Journal of Neuroscience | volume = 41 | issue = 9 | pages = 1113–25 | date = May 2015 | pmid = 25761903 | doi = 10.1111/ejn.12872 | s2cid = 24099106 }}</ref><ref name="pmid22860091">{{cite journal | vauthors = Jiang H, He C, Geng S, Sheng H, Shen X, Zhang X, Li H, Zhu S, Chen X, Yang C, Gao H | title = RhoT1 and Smad4 are correlated with lymph node metastasis and overall survival in pancreatic cancer | journal = PLOS ONE | volume = 7 | issue = 7 | article-number = e42234 | date = 2012 | pmid = 22860091 | doi = 10.1371/journal.pone.0042234 | pmc=3409151| bibcode = 2012PLoSO...742234J | doi-access = free }}</ref>
==Structure== In mammals, RHOT1 is one of two Miro isoforms. Both isoforms share a structure consisting of two EF-hand motifs linking two GTP-binding domains and a C-terminal transmembrane domain that attaches the protein to the [[outer mitochondrial membrane]] (OMM).<ref name="pmid23732472"/><ref name="pmid16630562">{{cite journal | vauthors = Fransson S, Ruusala A, Aspenström P | title = The atypical Rho GTPases Miro-1 and Miro-2 have essential roles in mitochondrial trafficking | journal = Biochemical and Biophysical Research Communications | volume = 344 | issue = 2 | pages = 500–10 | date = Jun 2006 | pmid = 16630562 | doi = 10.1016/j.bbrc.2006.03.163 | bibcode = 2006BBRC..344..500F }}</ref> The EF-hand motifs serve as binding sites for the adaptor protein Milton and the [[KIF5B|kinesin heavy chain]].<ref name="pmid24492963">{{cite journal | vauthors = Morlino G, Barreiro O, Baixauli F, Robles-Valero J, González-Granado JM, Villa-Bellosta R, Cuenca J, Sánchez-Sorzano CO, Veiga E, Martín-Cófreces NB, Sánchez-Madrid F | title = Miro-1 links mitochondria and microtubule Dynein motors to control lymphocyte migration and polarity | journal = Molecular and Cellular Biology | volume = 34 | issue = 8 | pages = 1412–26 | date = Apr 2014 | pmid = 24492963 | doi = 10.1128/MCB.01177-13 | pmc=3993592| url = https://repositorio.uam.es/bitstream/10486/664660/1/links_morino_MCB_2014.pdf }}</ref> These domains can also bind calcium ions, and the binding results in a conformational change that dissociates the mitochondrial surface from kinesin.<ref name="pmid23732472"/><ref name="pmid16630562"/>
== Function == RHOT1 is a member of the [[Rho family of GTPases|Rho GTPase family]] and one of two isoforms of the protein Miro: RHOT1 (Miro1) and [[RHOT2]] (Miro2).<ref name="pmid23732472"/><ref name="pmid24492963"/> Compared to the rest of the Rho GTPase family, the Miro isoforms are considered atypical due to their different regulation.<ref name="pmid22860091"/> Moreover, the Miro isoforms are only expressed in the mitochondria.<ref name="pmid24092329">{{cite journal | vauthors = Ogawa F, Malavasi EL, Crummie DK, Eykelenboom JE, Soares DC, Mackie S, Porteous DJ, Millar JK | title = DISC1 complexes with TRAK1 and Miro1 to modulate anterograde axonal mitochondrial trafficking | journal = Human Molecular Genetics | volume = 23 | issue = 4 | pages = 906–19 | date = Feb 2014 | pmid = 24092329 | doi = 10.1093/hmg/ddt485 | pmc=3900104}}</ref>
Miro associates with Milton ([[TRAK1]]/[[TRAK2|2]]) and the motor proteins [[kinesin]] and [[dynein]] to form the mitochondrial motor/adaptor complex. Miro functions to tether the complex to the mitochondrion while the complex transports the mitochondrion via [[microtubule]]s within cells.<ref name="pmid23732472"/><ref name="pmid25761903"/> Though Miro has been predominantly studied in [[neuron]]s, the protein has also been observed to participate in the transport of mitochondria in [[lymphocyte]]s toward [[inflammation|inflamed]] endothelia.<ref name="pmid24492963"/>
The motor/adaptor complex is regulated by calcium ion levels. At high concentrations, calcium ions arrest mitochondrial transport by binding Miro, causing the complex to detach from the organelle. Considering that physiological factors such as activation of [[glutamate receptor]]s in dendrites, [[action potential]]s in axons, and neuromodulators may elevate calcium ion levels, this regulatory mechanism likely serves to keep mitochondria in such areas to provide calcium ion buffering and active export and, thus, maintain homeostasis.<ref name="pmid23732472"/>
In addition, Miro regulates [[mitochondrial fusion]] and [[mitophagy]] in conjunction with [[mitofusin]]. According to one model, damaged mitochondria are sequestered from healthy mitochondria by the degradation of Miro and mitofusin. Miro degradation halts their movement while mitofusin degradation prevents them from fusing with healthy mitochondria, thus facilitating their clearance by autophagosomes.<ref name="pmid23732472"/>
Though the exact mechanisms remain to be elucidated, RHOT1 has been implicated in promoting [[caspase]]-dependent apoptosis.<ref name="pmid12482879"/>
== Clinical significance ==
Studies indicate that Miro may be involved in PD.<ref name="pmid25761903"/> In neurons, Miro interacts with two key proteins involved in PD, PINK1 and Parkin.<ref name="pmid23732472"/> Following depolarization of the mitochondria, PINK1 phosphorylates Miro at multiple sites, including S156, and Parkin ubiquitinates Miro, targeting it for proteasomal degradation.<ref name="pmid23732472"/><ref name="pmid25761903"/> Degradation of Miro then halts mitochondrial transport.<ref name="pmid23732472"/>
Though the Rho GTPase family is closely associated with cancer progression, there are few studies demonstrating such association with the atypical Miro proteins. Nonetheless, RHOT1 has been implicated in pancreatic cancer as a tumor suppressor through its regulation of mitochondrial homeostasis and apoptosis. Thus, this protein could serve as a therapeutic target for cancer treatment.<ref name="pmid22860091"/>
== Interactions ==
RHOT1 has been shown to [[Protein-protein interaction|interact]] with: * [[ARMCX3|ALEX3]],<ref name="pmid23732472"/> * [[DISC1]],<ref name="pmid24092329"/> * [[Dynein]],<ref name="pmid23732472"/> * [[MGARP|HUMMR]],<ref name="pmid23732472"/> * [[Kinesin|kinesin heavy chain]] (KHC),<ref name="pmid23732472"/> * Mitofusin ([[MFN1]]/[[MFN2]]),<ref name="pmid23732472"/> * Milton ([[TRAK1]]/[[TRAK2]]),<ref name="pmid23732472"/> * [[Parkin (ligase)|Parkin]],<ref name="pmid23732472"/> * [[PINK1]],<ref name="pmid23732472"/> and * [[OGT (gene)|OGT]].<ref name="pmid23732472"/>
== References == {{reflist|33em}}
== Further reading == {{refbegin|33em}} * {{cite journal | vauthors = Hartley JL, Temple GF, Brasch MA | title = DNA cloning using in vitro site-specific recombination | journal = Genome Research | volume = 10 | issue = 11 | pages = 1788–95 | date = Nov 2000 | pmid = 11076863 | pmc = 310948 | doi = 10.1101/gr.143000 }} * {{cite journal | vauthors = Wiemann S, Weil B, Wellenreuther R, Gassenhuber J, Glassl S, Ansorge W, Böcher M, Blöcker H, Bauersachs S, Blum H, Lauber J, Düsterhöft A, Beyer A, Köhrer K, Strack N, Mewes HW, Ottenwälder B, Obermaier B, Tampe J, Heubner D, Wambutt R, Korn B, Klein M, Poustka A | title = Toward a catalog of human genes and proteins: sequencing and analysis of 500 novel complete protein coding human cDNAs | journal = Genome Research | volume = 11 | issue = 3 | pages = 422–35 | date = Mar 2001 | pmid = 11230166 | pmc = 311072 | doi = 10.1101/gr.GR1547R }} * {{cite journal | vauthors = Aspenström P, Fransson A, Saras J | title = Rho GTPases have diverse effects on the organization of the actin filament system | journal = The Biochemical Journal | volume = 377 | issue = Pt 2 | pages = 327–37 | date = Jan 2004 | pmid = 14521508 | pmc = 1223866 | doi = 10.1042/BJ20031041 }} * {{cite journal | vauthors = Brandenberger R, Wei H, Zhang S, Lei S, Murage J, Fisk GJ, Li Y, Xu C, Fang R, Guegler K, Rao MS, Mandalam R, Lebkowski J, Stanton LW | title = Transcriptome characterization elucidates signaling networks that control human ES cell growth and differentiation | journal = Nature Biotechnology | volume = 22 | issue = 6 | pages = 707–16 | date = Jun 2004 | pmid = 15146197 | doi = 10.1038/nbt971 | s2cid = 27764390 }} * {{cite journal | vauthors = Wiemann S, Arlt D, Huber W, Wellenreuther R, Schleeger S, Mehrle A, Bechtel S, Sauermann M, Korf U, Pepperkok R, Sültmann H, Poustka A | title = From ORFeome to biology: a functional genomics pipeline | journal = Genome Research | volume = 14 | issue = 10B | pages = 2136–44 | date = Oct 2004 | pmid = 15489336 | pmc = 528930 | doi = 10.1101/gr.2576704 }} * {{cite journal | vauthors = Mehrle A, Rosenfelder H, Schupp I, del Val C, Arlt D, Hahne F, Bechtel S, Simpson J, Hofmann O, Hide W, Glatting KH, Huber W, Pepperkok R, Poustka A, Wiemann S | title = The LIFEdb database in 2006 | journal = Nucleic Acids Research | volume = 34 | issue = Database issue | pages = D415-8 | date = Jan 2006 | pmid = 16381901 | pmc = 1347501 | doi = 10.1093/nar/gkj139 }} * {{cite journal | vauthors = Fransson S, Ruusala A, Aspenström P | title = The atypical Rho GTPases Miro-1 and Miro-2 have essential roles in mitochondrial trafficking | journal = Biochemical and Biophysical Research Communications | volume = 344 | issue = 2 | pages = 500–10 | date = Jun 2006 | pmid = 16630562 | doi = 10.1016/j.bbrc.2006.03.163 | bibcode = 2006BBRC..344..500F }} {{refend}}
[[Category:Genes mutated in mice]] [[Category:EF-hand-containing proteins]]