Mitochondrial Rho GTPase 2 is an
enzyme that in humans is encoded by the ''RHOT2''
gene.
As a
Miro protein
isoform, the protein facilitates mitochondrial transport by attaching the
mitochondria
A mitochondrion (; ) is an organelle found in the Cell (biology), cells of most Eukaryotes, such as animals, plants and Fungus, fungi. Mitochondria have a double lipid bilayer, membrane structure and use aerobic respiration to generate adenosi ...
to the motor/adaptor complex.
Through its key role in mitochondrial transport, RHOT2 is involved in mitochondrial
homeostasis and
apoptosis
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
, as well as
Parkinson’s disease (PD).
Structure
In mammals, RHOT2 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
A mitochondrion (; ) is an organelle found in the cells of most Eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is used t ...
(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
RHOT2 is a member of the
Rho GTPase family and one of two isoforms of the protein Miro:
RHOT1
Mitochondrial Rho GTPase 1 (MIRO1) is an enzyme that in humans is encoded by the ''RHOT1'' gene on chromosome 17. As a Miro (protein), Miro protein isoform, the protein facilitates mitochondrial transport by attaching the mitochondria to the motor ...
(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
Dyneins are a family of cytoskeletal motor proteins that move along microtubules in cells. They convert the chemical energy stored in ATP to mechanical work. Dynein transports various cellular cargos, provides forces and displacements importa ...
to form the mitochondrial motor/adaptor complex. Miro functions to tether the complex to the mitochondrion while the complex transports the mitochondrion via
microtubule
Microtubules are polymers of tubulin that form part of the cytoskeleton and provide structure and shape to eukaryotic cells. Microtubules can be as long as 50 micrometres, as wide as 23 to 27 nm and have an inner diameter between 11 an ...
s 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.
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.
Interactions
RHOT1 has been shown to
interact
Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizati ...
with:
*
ALEX3,
*
DISC1,
*
Dynein
Dyneins are a family of cytoskeletal motor proteins that move along microtubules in cells. They convert the chemical energy stored in ATP to mechanical work. Dynein transports various cellular cargos, provides forces and displacements importa ...
,
*
HUMMR,
*
kinesin heavy chain (KHC),
* Mitofusin (
MFN1
Mitofusin-1 is a protein that in humans is encoded by the ''MFN1'' gene.
The protein encoded by this gene is a mediator of mitochondrial fusion. This protein and mitofusin 2 are homologs of the ''Drosophila
''Drosophila'' () is a genus of fl ...
/
MFN2
Mitofusin-2 is a protein that in humans is encoded by the ''MFN2'' gene. Mitofusins are GTPases embedded in the outer membrane of the mitochondria. In mammals MFN1 and MFN2 are essential for mitochondrial fusion. In addition to the mitofusins, OP ...
),
* Milton (
TRAK1/
TRAK2
Trafficking kinesin-binding protein 2 is a protein that in humans is encoded by the ''TRAK2'' gene.
Interactions
TRAK2 has been shown to interact with Kir2.1
The Kir2.1 inward-rectifier potassium channel is a lipid-gated ion channel encoded ...
),
*
Parkin,
*
PINK1
PTEN-induced kinase 1 (PINK1) is a mitochondrial serine/threonine-protein kinase encoded by the ''PINK1'' gene.
It is thought to protect cells from stress-induced mitochondrial dysfunction. PINK1 activity causes the parkin protein to bind to d ...
,
and
*
OGT.
References
Further reading
*
*
*
*
*
*
{{refend
Enzymes
EF-hand-containing proteins