RHOT1
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Mitochondrial Rho GTPase 1 (MIRO1) is an
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
Function
RHOT1 is a member of the Rho GTPase family and one of two isoforms of the protein Miro: RHOT1 (Miro1) and RHOT2 (Miro2).[7][11] Compared to the rest of the Rho GTPase family, the Miro isoforms are considered atypical due to their different regulation.[9] Moreover, the Miro isoforms are only expressed in the mitochondria.[12]
Miro associates with Milton (TRAK1/2) 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 microtubules within cells.[7][8] Though Miro has been predominantly studied in neurons, the protein has also been observed to participate in the transport of mitochondria in lymphocytes toward inflamed endothelia.[11]
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 receptors in dendrites, action potentials 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.[7]
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.[7]
Though the exact mechanisms remain to be elucidated, RHOT1 has been implicated in promoting caspase-dependent apoptosis.[5]
Clinical significance
Studies indicate that Miro may be involved in PD.[8] In neurons, Miro interacts with two key proteins involved in PD, PINK1 and Parkin.[7] Following depolarization of the mitochondria, PINK1 phosphorylates Miro at multiple sites, including S156, and Parkin ubiquitinates Miro, targeting it for proteasomal degradation.[7][8] Degradation of Miro then halts mitochondrial transport.[7]
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.[9]
Interactions
RHOT1 has been shown to
- ALEX3,[7]
- DISC1,[12]
- Dynein,[7]
- HUMMR,[7]
- kinesin heavy chain (KHC),[7]
- Mitofusin (MFN1/MFN2),[7]
- Milton (TRAK1/TRAK2),[7]
- Parkin,[7]
- PINK1,[7] and
- OGT.[7]
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000126858 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000017686 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ PMID 12482879.
- ^ "Entrez Gene: RHOT1 ras homolog gene family, member T1".
- ^ PMID 23732472.
- ^ S2CID 24099106.
- ^ PMID 22860091.
- ^ PMID 16630562.
- ^ PMID 24492963.
- ^ PMID 24092329.
Further reading
- Hartley JL, Temple GF, Brasch MA (Nov 2000). "DNA cloning using in vitro site-specific recombination". Genome Research. 10 (11): 1788–95. PMID 11076863.
- 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 (Mar 2001). "Toward a catalog of human genes and proteins: sequencing and analysis of 500 novel complete protein coding human cDNAs". Genome Research. 11 (3): 422–35. PMID 11230166.
- Aspenström P, Fransson A, Saras J (Jan 2004). "Rho GTPases have diverse effects on the organization of the actin filament system". The Biochemical Journal. 377 (Pt 2): 327–37. PMID 14521508.
- 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 (Jun 2004). "Transcriptome characterization elucidates signaling networks that control human ES cell growth and differentiation". Nature Biotechnology. 22 (6): 707–16. S2CID 27764390.
- Wiemann S, Arlt D, Huber W, Wellenreuther R, Schleeger S, Mehrle A, Bechtel S, Sauermann M, Korf U, Pepperkok R, Sültmann H, Poustka A (Oct 2004). "From ORFeome to biology: a functional genomics pipeline". Genome Research. 14 (10B): 2136–44. PMID 15489336.
- 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 (Jan 2006). "The LIFEdb database in 2006". Nucleic Acids Research. 34 (Database issue): D415-8. PMID 16381901.
- Fransson S, Ruusala A, Aspenström P (Jun 2006). "The atypical Rho GTPases Miro-1 and Miro-2 have essential roles in mitochondrial trafficking". Biochemical and Biophysical Research Communications. 344 (2): 500–10. PMID 16630562.