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Official Full Name
optic atrophy 1 (autosomal dominant)
This gene product is a nuclear-encoded mitochondrial protein with similarity to dynamin-related GTPases. It is a component of the mitochondrial network. 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. Multiple transcript variants encoding different isoforms have been found for this gene.
OPA1; optic atrophy 1 (autosomal dominant); dynamin-like 120 kDa protein, mitochondrial; dynamin like guanosine triphosphatase; FLJ12460; KIAA0567; MGM1; mitochondrial dynamin like GTPase; NPG; NTG; optic atrophy protein 1; mitochondrial dynamin-like GTPa; optic atrophy protein 1 homolog; fk62d06; zgc:92092; wu:fb77a10; wu:fk62d06

GTPase optic atrophy type 1 (OPA1) gene encodes a mitochondrial protein localized in the inter-membrane space (IMS) and associated to mitochondrial membranes. OPA1 is essential for adapting mitochondrial function and preserving cellular health. OPA1 governs the delicate balance between fusion and fission in the dynamic mitochondrial network. A disturbance of this balance, often observed under stress and pathologic conditions, causes mitochondrial fragmentation and can ultimately result in cell death. In recent years, a growing number of evidences suggest that the prevention of OMA1-mediated OPA1 processing and mitochondrial fragmentation might thus offer the exciting therapeutic potential for human diseases associated with mitochondrial dysfunction.

OPA1 expression

OPA1, and its yeast orthologues Mgm1p in Saccharomyces cerevisiae and Msp1p in Schizosaccharomyces pombe, belongs to the dynamins’ family; with which it shares three conserved regions: a GTPase domain, a middle domain and a carboxy-terminal coiled-coil domain (CC-II) also called GTPase effector domain (GED). The latter is involved in the oligomerization and activation of the dynamins. The amino-terminal region of OPA1, preceding the GTPase domain, displays a mitochondrial import sequence (MIS) followed by a predicted transmembrane domain (TM1) and a coiled-coil domain (CC-I) located downstream of alternatively spliced exons. In humans, OPA1 ORF is built from 30 exons, 3 of which are alternatively spliced leading to 8 mRNA.

OPA1 and mitochondrial fusion

The delicate balance between fission and fusion is struck by the tight regulation of several dynamin-related proteins that are localized at the inner membrane (IMM) and outer membrane (OMM) (Figure 1). They all share a highly conserved GTPase domain and possess the ability to self-assemble, hydrolyze GTP and remodel membranes. At the OMM, mitochondrial fission is orchestrated by the mitochondrial recruitment and assembly of cytosolic dynamin-related protein 1 (DRP1, also known as DNM1L) into oligomers at sites of scission.

Figure 1. OPA1 regulates mitochondrial morphology and dynamics.

Loss of function of OPA1 by RNAi or gene knockout, or of Mgm1p and Msp1p, causes fragmentation of the tubular mitochondrial reticulum. Conversely, over-production of this protein promotes mitochondrial elongation in cells where mitochondria are punctuated. Surprisingly, over-expression of the dynamin in cells with tubular mitochondria causes mitochondrial fragmentation. However, such cells still possess a normal mitochondrial fusion activity. The profusion activity of OPA1 is further confirmed by experiments showing that mitochondrial fusion is impaired in OPA1-depleted or Opa1−/− cells. Interestingly, levels of OPA1 can differentially influence two types of fusion: a “transient fusion” that result in the rapid exchange of soluble components without affecting the morphology of mitochondria and a “complete fusion” that permits the exchange of all mitochondrial components and affect mitochondrial morphology.

OPA1 and disease

OPA1 was named so after its genetic mutation was shown to be the main cause of autosomal dominant optic atrophy (ADOA). This optic neuropathy is characterized by a destruction of retinal ganglion cells and the optic nerve, resulting in progressive vision loss. Although OPA1 is highly expressed in the retina, it is broadly expressed throughout the body and this might reflect the multiple disorders that have presented themselves in patients harboring heterozygous mutations of OPA1, including deafness and dementia. Until recently, all OPA1 mutations found in patients have been identified as heterozygous, with the only homozygous OPA1 mutation causing early-onset encephalomyopathy, cardiomyopathy and death during infancy.

In the last years, some invertebrate models bearing OPA1 mutations have been developed. In Caenorhabditis elegans mutations of the OPA1 orthologue, eat-3, cause mitochondrial fragmentation and inner membrane septa accumulation in matrix, both suggesting defect in fusion, as well as hypersensitivity to oxidative stress but no evidence for increased cell death. Homozygous mutations of dOpa1, the drosophila ortholog of OPA1, result in embryonic lethality and cause rough and glossy eyes phenotypes in somatic clones of adult flies by two distinct pathogenic pathways. Heterozygous mutations result in a shortened lifespan, increased production of ROS, sensitivity to oxidative stress, defects in the activity of respiratory chain complexes, aberrant mitochondrial structures as well as skeletal muscle, heart and eyes dysfunctions of which the latter is partially reversed by antioxidant treatments. In accordance, recent studies show that OPA1 mutations affect other organs besides the retina in human and mouse. These data suggest that OPA1 mutations could cause multiple organ abnormalities and furthermore indicate that the pathogenesis could be organ specific.

Exciting progress continues to improve our understanding of how the proteolytic processing of OPA1 is central to its function. It would be fascinating to discover whether preventing stress-induced OPA1 processing by OMA1 can improve the phenotypes of other mitochondrial-dysfunction-associated pathologies. However, targeting OMA1 for therapeutic use would require greater understanding of the role of OMA1-mediated OPA1 processing for mitochondrial quality control under conditions of transient stress and would also benefit from a greater exploration of additional substrates in mammalian models. In any case, further steps can now be taken to explore the therapeutic potential of preventing excessive stress-induced mitochondrial fragmentation in different tissues with a goal to eventually alleviate the severe symptoms of human diseases that are associated with mitochondrial dysfunction.


  1. Macvicar T, Langer T. OPA1 processing in cell death and disease - the long and short of it. Journal of Cell Science, 2016, 129(12):2297.
  2. Bertholet A M, et al. OPA1 loss of function affects in vitro neuronal maturation. Brain, 2013, 136(5):1518-1533.
  3. Williams P A, et al. Opa1 is essential for retinal ganglion cell synaptic architecture and connectivity. Brain, 2012, 135(2):493-505.
  4. Landes T, et al. OPA1 (dys)functions. Seminars in Cell & Developmental Biology, 2010, 21(6):593-598.
  5. Carelli V, et al. Syndromic parkinsonism and dementia associated with OPA1 missense mutations. Annals of Neurology, 2015, 78(1):21-38.
  6. Spiegel R, et al. Fatal infantile mitochondrial encephalomyopathy, hypertrophic cardiomyopathy and optic atrophy associated with a homozygous OPA1 mutation. Journal of Medical Genetics, 2016, 53(2):127-131.

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