RHOT1

VALUE_ERROR (nil)
Identifiers
Aliases
External IDs	GeneCards: [1]
Orthologs
Species	Human	Mouse
Entrez	n/a	n/a
Ensembl	n/a	n/a
UniProt	n/a	n/a
RefSeq (mRNA)	n/a	n/a
RefSeq (protein)	n/a	n/a
Location (UCSC)	n/a	n/a
PubMed search	n/a	n/a
Wikidata
View/Edit Human

Mitochondrial Rho GTPase 1 (MIRO1) is an enzyme that in humans is encoded by the RHOT1 gene on chromosome 17. As a Miro protein isoform, the protein facilitates mitochondrial transport by attaching the mitochondria to the motor/adaptor complex. Through its key role in mitochondrial transport, RHOT1 is involved in mitochondrial homeostasis and apoptosis, as well as Parkinson’s disease (PD) and cancer.

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). The EF-hand motifs serve as binding sites for the adaptor protein Milton and the kinesin heavy chain. These domains can also bind calcium ions, and the binding results in a conformational change that dissociates the mitochondrial surface from kinesin.

Function

RHOT1 is a member of the Rho GTPase family and one of two isoforms of the protein Miro: RHOT1 (Miro1) and RHOT2 (Miro2). Compared to the rest of the Rho GTPase family, the Miro isoforms are considered atypical due to their different regulation. Moreover, the Miro isoforms are only expressed in the mitochondria.

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. 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.

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.

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.

Though the exact mechanisms remain to be elucidated, RHOT1 has been implicated in promoting caspase-dependent apoptosis.

Clinical significance

Studies indicate that Miro may be involved in PD. In neurons, Miro interacts with two key proteins involved in PD, PINK1 and Parkin. Following depolarization of the mitochondria, PINK1 phosphorylates Miro at multiple sites, including S156, and Parkin ubiquitinates Miro, targeting it for proteasomal degradation. Degradation of Miro then halts mitochondrial transport.

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.

Model organisms

Rhot1 knockout mouse phenotype

Characteristic	Phenotype
Homozygote viability	Abnormal
Recessive lethal study	Normal
Fertility	Normal
Body weight	Normal
Anxiety	Normal
Neurological assessment	Normal
Grip strength	Normal
Hot plate	Normal
Dysmorphology	Normal
Indirect calorimetry	Normal
Glucose tolerance test	Normal
Auditory brainstem response	Normal
DEXA	Normal
Radiography	Normal
Body temperature	Normal
Eye morphology	Normal
Clinical chemistry	Normal
Plasma immunoglobulins	Normal
Haematology	Normal
Peripheral blood lymphocytes	Normal
Micronucleus test	Normal
Heart weight	Normal
Skin Histopathology	Normal
Brain histopathology	Normal
Salmonella infection	Normal
Citrobacter infection	Normal
All tests and analysis from

Model organisms have been used in the study of RHOT1 function. A conditional knockout mouse line, called Rhot1^{tm1a(EUCOMM)Wtsi} was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.

Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty six tests were carried out on mutant mice and one significant abnormality was observed: no homozygous mutants survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice and no further abnormalities were observed.

Interactions

RHOT1 has been shown to interact with:

• ALEX3,
• DISC1,
• Dynein,
• HUMMR,
• kinesin heavy chain (KHC),
• Mitofusin (MFN1/MFN2),
• Milton (TRAK1/TRAK2),
• Parkin,
• PINK1, and
• OGT.

Further reading

• Hartley JL, Temple GF, Brasch MA (Nov 2000). "DNA cloning using in vitro site-specific recombination". Genome Research. 10 (11): 1788–95. doi:10.1101/gr.143000. PMC 310948. 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. doi:10.1101/gr.GR1547R. PMC 311072. 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. doi:10.1042/BJ20031041. PMC 1223866. 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. doi:10.1038/nbt971. PMID 15146197.
• 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. doi:10.1101/gr.2576704. PMC 528930. 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. doi:10.1093/nar/gkj139. PMC 1347501. 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. doi:10.1016/j.bbrc.2006.03.163. PMID 16630562.