Dynamin-like 120 KDa Protein
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Dynamin-like 120 kDa protein, mitochondrial is a
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...
that in humans is encoded by the ''OPA1''
gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
. This protein regulates mitochondrial fusion and cristae structure in the
inner mitochondrial membrane The inner mitochondrial membrane (IMM) is the mitochondrial membrane which separates the mitochondrial matrix from the intermembrane space. Structure The structure of the inner mitochondrial membrane is extensively folded and compartmentalized. T ...
(IMM) and contributes to ATP synthesis and apoptosis, and small, round mitochondria. Mutations in this gene have been implicated in dominant optic atrophy (DOA), leading to loss in vision, hearing, muscle contraction, and related dysfunctions.


Structure

Eight transcript variants encoding different isoforms, resulting from alternative splicing of exon 4 and two novel exons named 4b and 5b, have been reported for this gene. They fall under two types of isoforms: long isoforms (L-OPA1), which attach to the IMM, and short isoforms (S-OPA1), which localize to the
intermembrane space The intermembrane space (IMS) is the space occurring between or involving two or more membranes. In cell biology, it is most commonly described as the region between the Inner mitochondrial membrane, inner membrane and the Outer mitochondrial memb ...
(IMS) near the outer mitochondrial membrane (OMM). S-OPA1 is formed by proteolysis of L-OPA1 at the cleavage sites S1 and S2, removing the transmembrane domain. The ''OPA1'' transcript may be alternatively spliced to incorporate a poison exon between exons 5 and 6 or between exons 5b and 6.


Function

This gene product is a nuclear-encoded mitochondrial protein with similarity to dynamin-related GTPases. It is a component of the mitochondrial network. The OPA1 protein localizes to the inner mitochondrial membrane, where it regulates mitochondrial fusion and cristae structure. OPA1 mediates mitochondrial fusion in cooperation with mitofusins 1 and 2 and participates in cristae remodeling by the oligomerization of two L-OPA1 and one S-OPA1, which then interact with other protein complexes to alter cristae structure. Its cristae regulating function also contributes to its role in oxidative phosphorylation and apoptosis, as it is required to maintain mitochondrial activity during low-energy substrate availability. Moreover, stabilization of mitochondrial cristae by OPA1 protects against mitochondrial dysfunction, cytochrome c release, and
reactive oxygen species In chemistry and biology, reactive oxygen species (ROS) are highly Reactivity (chemistry), reactive chemicals formed from diatomic oxygen (), water, and hydrogen peroxide. Some prominent ROS are hydroperoxide (H2O2), superoxide (O2−), hydroxyl ...
production, thus preventing cell death. Mitochondrial SLC25A transporters can detect these low levels and stimulate OPA1 oligomerization, leading to tightening of the cristae, enhanced assembly of ATP synthase, and increased ATP production. Stress from an apoptotic response can interfere with OPA1 oligomerization and prevent mitochondrial fusion.


Clinical significance

Mutations in this gene have been associated with optic atrophy type 1, which is a dominantly inherited optic neuropathy resulting in progressive loss of visual acuity, leading in many cases to legal blindness. Dominant optic atrophy (DOA) in particular has been traced to mutations in the GTPase domain of OPA1, leading to sensorineural hearing loss, ataxia, sensorimotor neuropathy, progressive external ophthalmoplegia, and mitochondrial myopathy. As the mutations can lead to degeneration of auditory nerve fibres, cochlear implants provide a therapeutic means to improve hearing thresholds and speech perception in patients with OPA1-derived hearing loss. Mitochondrial fusion involving OPA1 and MFN2 may be associated with
Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a neurodegenerative disease primarily of the central nervous system, affecting both motor system, motor and non-motor systems. Symptoms typically develop gradually and non-motor issues become ...
. Stoke Therapeutics is evaluating the splice-switching antisense oligonucleotide STK-002 as a potential treatment for DOA. STK-002 reduces poison exon inclusion in the ''OPA1'' transcript, leading to increased OPA1 protein levels.


Interactions

OPA1 has been shown to interact with: * Adenonucleotide transporters, *
ATP synthase ATP synthase is an enzyme that catalyzes the formation of the energy storage molecule adenosine triphosphate (ATP) using adenosine diphosphate (ADP) and inorganic phosphate (Pi). ATP synthase is a molecular machine. The overall reaction catalyzed ...
, * CHCHD3, * Mitofilin, * Prohibitin, * SAMM50, and * SLC25A.


See also

* Kjer's optic neuropathy


References


Further reading

* * * * * * * * * * * * * * * * * * *{{refend


External links


GeneReview/NCBI/NIH/UW entry on Optic Atrophy Type 1association kjer-france