Dynamin-like 120 kDa protein, mitochondrial is a protein that in humans is encoded by the OPA1 gene. [5] [6] This protein regulates mitochondrial fusion and cristae structure in the inner mitochondrial membrane (IMM) and contributes to ATP synthesis and apoptosis, [7] [8] [9] and small, round mitochondria. [10] Mutations in this gene have been implicated in dominant optic atrophy (DOA), leading to loss in vision, hearing, muscle contraction, and related dysfunctions. [6] [7] [11]
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. [6] 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 (IMS) near the outer mitochondrial membrane (OMM). [12] S-OPA1 is formed by proteolysis of L-OPA1 at the cleavage sites S1 and S2, removing the transmembrane domain. [9]
The OPA1 transcript may be alternatively spliced to incorporate a poison exon between exons 5 and 6 or between exons 5b and 6. [13]
This gene product is a nuclear-encoded mitochondrial protein with similarity to dynamin-related GTPases. It is a component of the mitochondrial network. [6] The OPA1 protein localizes to the inner mitochondrial membrane, where it regulates mitochondrial fusion and cristae structure. [7] 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. [8] [14] 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. [7] [8] [9] Moreover, stabilization of mitochondrial cristae by OPA1 protects against mitochondrial dysfunction, cytochrome c release, and reactive oxygen species production, thus preventing cell death. [15] 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. [8] Stress from an apoptotic response can interfere with OPA1 oligomerization and prevent mitochondrial fusion. [9]
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. [6] 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. [7] [11] 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. [7]
Mitochondrial fusion involving OPA1 and MFN2 may be associated with Parkinson's disease. [11]
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. [13]
OPA1 has been shown to interact with:
Wolfram syndrome, also called DIDMOAD, is a rare autosomal-recessive genetic disorder that causes childhood-onset diabetes mellitus, optic atrophy, and deafness as well as various other possible disorders including neurodegeneration. Symptoms can start to appear as early as childhood to adult years. There is a 25% recurrence risk in children.
Behr syndrome is characterized by the association of early-onset optic atrophy with spinocerebellar degeneration resulting in ataxia, pyramidal signs, peripheral neuropathy and developmental delay.
Dominant optic atrophy (DOA), or autosomal dominant optic atrophy (ADOA), (Kjer's type) is an autosomally inherited disease that affects the optic nerves, causing reduced visual acuity and blindness beginning in childhood. However, the disease can seem to re-present a second time with further vision loss due to the early onset of presbyopia symptoms (i.e., difficulty in viewing objects up close). DOA is characterized as affecting neurons called retinal ganglion cells (RGCs). This condition is due to mitochondrial dysfunction mediating the death of optic nerve fibers. The RGCs axons form the optic nerve. Therefore, the disease can be considered of the central nervous system. Dominant optic atrophy was first described clinically by Batten in 1896 and named Kjer’s optic neuropathy in 1959 after Danish ophthalmologist Poul Kjer, who studied 19 families with the disease. Although dominant optic atrophy is the most common autosomally inherited optic neuropathy (i.e., disease of the optic nerves), it is often misdiagnosed.
Dynamin is a GTPase responsible for endocytosis in the eukaryotic cell. Dynamin is part of the "dynamin superfamily", which includes classical dynamins, dynamin-like proteins, Mx proteins, OPA1, mitofusins, and GBPs. Members of the dynamin family are principally involved in the scission of newly formed vesicles from the membrane of one cellular compartment and their targeting to, and fusion with, another compartment, both at the cell surface as well as at the Golgi apparatus. Dynamin family members also play a role in many processes including division of organelles, cytokinesis and microbial pathogen resistance.
Costeff syndrome, or 3-methylglutaconic aciduria type III, is a genetic disorder caused by mutations in the OPA3 gene. It is typically associated with the onset of visual deterioration in early childhood followed by the development of movement problems and motor disability in later childhood, occasionally along with mild cases of cognitive deficiency. The disorder is named after Hanan Costeff, the doctor who first described the syndrome in 1989.
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, OPA1 regulates inner mitochondrial membrane fusion, and DRP1 is responsible for mitochondrial fission.
Dynamin-2 is a protein that in humans is encoded by the DNM2 gene.
X-linked retinitis pigmentosa GTPase regulator is a GTPase-binding protein that in humans is encoded by the RPGR gene. The gene is located on the X-chromosome and is commonly associated with X-linked retinitis pigmentosa (XLRP). In photoreceptor cells, RPGR is localized in the connecting cilium which connects the protein-synthesizing inner segment to the photosensitive outer segment and is involved in the modulation of cargo trafficked between the two segments.
Wolframin is a protein that in humans is encoded by the WFS1 gene.
Mitochondrial import inner membrane translocase subunit Tim8 A, also known as deafness-dystonia peptide or protein is an enzyme that in humans is encoded by the TIMM8A gene. This translocase has similarity to yeast mitochondrial proteins that are involved in the import of metabolite transporters from the cytoplasm into the mitochondrial inner membrane. The gene is mutated in deafness-dystonia syndrome and it is postulated that MTS/DFN-1 is a mitochondrial disease caused by a defective mitochondrial protein import system.
Dynamin-1-like protein is a GTPase that regulates mitochondrial fission. In humans, dynamin-1-like protein, which is typically referred to as dynamin-related protein 1 (Drp1), is encoded by the DNM1L gene and is part of the dynamin superfamily (DSP) family of proteins.
Optic atrophy 3 protein is a protein that in humans is encoded by the OPA3 gene.
ATP-dependent metalloprotease YME1L1 is an enzyme that in humans is encoded by the YME1L1 gene. YME1L1 belongs to the AAA family of ATPases and mainly functions in the maintenance of mitochondrial morphology. Mutations in this gene would cause infantile-onset mitochondriopathy.
Presenilins-associated rhomboid-like protein, mitochondrial (PSARL), also known as PINK1/PGAM5-associated rhomboid-like protease (PARL), is an inner mitochondrial membrane protein that in humans is encoded by the PARL gene on chromosome 3. It is a member of the rhomboid family of intramembrane serine proteases. This protein is involved in signal transduction and apoptosis, as well as neurodegenerative diseases and type 2 diabetes.
Paul Kjer is a Danish ophthalmologist who studied a condition in nineteen families that was characterized by infantile optic atrophy along with a dominant inheritance mode. In 1959, the condition was named Kjer's optic neuropathy in his honor.
Transmembrane protein 126A is a mitochondrial transmembrane protein of unknown function coded for by the TMEM126A gene.
Mitochondria are dynamic organelles with the ability to fuse and divide (fission), forming constantly changing tubular networks in most eukaryotic cells. These mitochondrial dynamics, first observed over a hundred years ago are important for the health of the cell, and defects in dynamics lead to genetic disorders. Through fusion, mitochondria can overcome the dangerous consequences of genetic malfunction. The process of mitochondrial fusion involves a variety of proteins that assist the cell throughout the series of events that form this process.
Luca Scorrano is an Italian biologist and professor of Biochemistry at the University of Padua as well as the former Scientific Director of the Veneto Institute of Molecular Medicine in Italy. He is known for his important contributions to the field of mitochondrial dynamics and the interface between mitochondria and the endoplasmic reticulum.
Coiled-coil-helix-coiled-coil-helix domain-containing protein 10, mitochondrial, also known as Protein N27C7-4 is a protein that in humans is encoded by the CHCHD10 gene.
Solute carrier family 25 member 46 is a protein that in humans is encoded by the SLC25A46 gene. This protein is a member of the SLC25 mitochondrial solute carrier family. It is a transmembrane protein located in the mitochondrial outer membrane involved in lipid transfer from the endoplasmic reticulum (ER) to mitochondria. Mutations in this gene result in neuropathy and optic atrophy.
