Optic atrophy 1

Optic atrophy 1 (autosomal dominant)
Identifiers
SymbolsOPA1 ; MGM1; NPG; NTG; largeG
External IDsOMIM: 605290 MGI: 1921393 HomoloGene: 14618 GeneCards: OPA1 Gene
EC number3.6.5.5
RNA expression pattern
More reference expression data
Orthologs
SpeciesHumanMouse
Entrez497674143
EnsemblENSG00000198836ENSMUSG00000038084
UniProtO60313P58281
RefSeq (mRNA)NM_015560NM_001199177
RefSeq (protein)NP_056375NP_001186106
Location (UCSC)Chr 3:
193.31 – 193.42 Mb		Chr 16:
29.58 – 29.65 Mb
PubMed search

Dynamin-like 120 kDa protein, mitochondrial is a protein that in humans is encoded by the OPA1 gene.[1][2] This protein regulates mitochondrial fusion and cristae structure in the inner mitochondrial membrane (IMM) and contributes to ATP synthesis and apoptosis.[3][4][5] Mutations in this gene have been implicated in dominant optic atrophy (DOA), leading to loss in vision, hearing, muscle contraction, and related dysfunctions.[2][3][6]

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.[2] 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).[7] S-OPA1 is formed by proteolysis of L-OPA1 at the cleavage sites S1 and S2, removing the transmembrane domain.[5]

Function

This gene product is a nuclear-encoded mitochondrial protein with similarity to dynamin-related GTPases. It is a component of the mitochondrial network.[2] The OPA1 protein localizes to the inner mitochondrial membrane, where it regulates mitochondrial fusion and cristae structure.[3] 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][4][4] 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.[3][4][5] 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.[4] Stress from an apoptotic response can interfere with OPA1 oligomerization and prevent mitochondrial fusion.[5]

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.[2] Dominant optic atrophy (DOA) in particular has been been traced to mutations in the GTPase domain of OPA1, leading to sensorineural hearing loss, ataxia, sensorimotor neuropathy, progressive external ophthalmoplegia, and mitochondrial myopathy.[3][6] 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.[3]

Mitochondrial fusion involving OPA1 and MFN2 may be associated with Parkinson’s disease.[6]

Interactions

OPA1 has been shown to interact with:

See also

References

  1. ↑ Votruba M, Moore AT, Bhattacharya SS (Jan 1998). "Demonstration of a founder effect and fine mapping of dominant optic atrophy locus on 3q28-qter by linkage disequilibrium method: a study of 38 British Isles pedigrees". Human Genetics 102 (1): 79–86. doi:10.1007/s004390050657. PMID 9490303.
  2. ↑ 2.0 2.1 2.2 2.3 2.4 "Entrez Gene: OPA1 optic atrophy 1 (autosomal dominant)".
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 Santarelli R, Rossi R, Scimemi P, Cama E, Valentino ML, La Morgia C et al. (Mar 2015). "OPA1-related auditory neuropathy: site of lesion and outcome of cochlear implantation". Brain 138 (Pt 3): 563–76. doi:10.1093/brain/awu378. PMID 25564500.
  4. ↑ 4.0 4.1 4.2 4.3 4.4 4.5 4.6 4.7 4.8 4.9 4.10 4.11 Patten DA, Wong J, Khacho M, Soubannier V, Mailloux RJ, Pilon-Larose K et al. (Nov 2014). "OPA1-dependent cristae modulation is essential for cellular adaptation to metabolic demand". The EMBO Journal 33 (22): 2676–91. doi:10.15252/embj.201488349. PMID 25298396.
  5. ↑ 5.0 5.1 5.2 5.3 Anand R, Wai T, Baker MJ, Kladt N, Schauss AC, Rugarli E et al. (Mar 2014). "The i-AAA protease YME1L and OMA1 cleave OPA1 to balance mitochondrial fusion and fission". The Journal of Cell Biology 204 (6): 919–29. doi:10.1083/jcb.201308006. PMID 24616225.
  6. ↑ 6.0 6.1 6.2 Carelli V, Musumeci O, Caporali L, Zanna C, La Morgia C, Del Dotto V et al. (Mar 2015). "Syndromic parkinsonism and dementia associated with OPA1 missense mutations". Annals of Neurology. doi:10.1002/ana.24410. PMID 25820230.
  7. ↑ Fülöp L, Rajki A, Katona D, Szanda G, Spät A (Dec 2013). "Extramitochondrial OPA1 and adrenocortical function". Molecular and Cellular Endocrinology 381 (1-2): 70–9. doi:10.1016/j.mce.2013.07.021. PMID 23906536.
  8. ↑ Fülöp L, Szanda G, Enyedi B, Várnai P, Spät A (2011). "The effect of OPA1 on mitochondrial Ca²⁺ signaling". PloS One 6 (9): e25199. doi:10.1371/journal.pone.0025199. PMID 21980395.

Further reading

  • Olichon A, Guillou E, Delettre C, Landes T, Arnauné-Pelloquin L, Emorine LJ et al. (2006). "Mitochondrial dynamics and disease, OPA1". Biochimica Et Biophysica Acta 1763 (5-6): 500–9. doi:10.1016/j.bbamcr.2006.04.003. PMID 16737747.
  • Pawlikowska P, Orzechowski A (2007). "[Role of transmembrane GTPases in mitochondrial morphology and activity]". Postepy Biochemii 53 (1): 53–9. PMID 17718388.
  • Nagase T, Ishikawa K, Miyajima N, Tanaka A, Kotani H, Nomura N et al. (Feb 1998). "Prediction of the coding sequences of unidentified human genes. IX. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro". DNA Research 5 (1): 31–9. doi:10.1093/dnares/5.1.31. PMID 9628581.
  • Johnston RL, Seller MJ, Behnam JT, Burdon MA, Spalton DJ (Jan 1999). "Dominant optic atrophy. Refining the clinical diagnostic criteria in light of genetic linkage studies". Ophthalmology 106 (1): 123–8. doi:10.1016/S0161-6420(99)90013-1. PMID 9917792.
  • Delettre C, Lenaers G, Griffoin JM, Gigarel N, Lorenzo C, Belenguer P et al. (Oct 2000). "Nuclear gene OPA1, encoding a mitochondrial dynamin-related protein, is mutated in dominant optic atrophy". Nature Genetics 26 (2): 207–10. doi:10.1038/79936. PMID 11017079.
  • Alexander C, Votruba M, Pesch UE, Thiselton DL, Mayer S, Moore A et al. (Oct 2000). "OPA1, encoding a dynamin-related GTPase, is mutated in autosomal dominant optic atrophy linked to chromosome 3q28". Nature Genetics 26 (2): 211–5. doi:10.1038/79944. PMID 11017080.
  • Toomes C, Marchbank NJ, Mackey DA, Craig JE, Newbury-Ecob RA, Bennett CP et al. (Jun 2001). "Spectrum, frequency and penetrance of OPA1 mutations in dominant optic atrophy". Human Molecular Genetics 10 (13): 1369–78. doi:10.1093/hmg/10.13.1369. PMID 11440989.
  • Thiselton DL, Alexander C, Morris A, Brooks S, Rosenberg T, Eiberg H et al. (Nov 2001). "A frameshift mutation in exon 28 of the OPA1 gene explains the high prevalence of dominant optic atrophy in the Danish population: evidence for a founder effect". Human Genetics 109 (5): 498–502. doi:10.1007/s004390100600. PMID 11735024.
  • Delettre C, Griffoin JM, Kaplan J, Dollfus H, Lorenz B, Faivre L et al. (Dec 2001). "Mutation spectrum and splicing variants in the OPA1 gene". Human Genetics 109 (6): 584–91. doi:10.1007/s00439-001-0633-y. PMID 11810270.
  • Aung T, Ocaka L, Ebenezer ND, Morris AG, Krawczak M, Thiselton DL et al. (Jan 2002). "A major marker for normal tension glaucoma: association with polymorphisms in the OPA1 gene". Human Genetics 110 (1): 52–6. doi:10.1007/s00439-001-0645-7. PMID 11810296.
  • Misaka T, Miyashita T, Kubo Y (May 2002). "Primary structure of a dynamin-related mouse mitochondrial GTPase and its distribution in brain, subcellular localization, and effect on mitochondrial morphology". The Journal of Biological Chemistry 277 (18): 15834–42. doi:10.1074/jbc.M109260200. PMID 11847212.
  • Thiselton DL, Alexander C, Taanman JW, Brooks S, Rosenberg T, Eiberg H et al. (Jun 2002). "A comprehensive survey of mutations in the OPA1 gene in patients with autosomal dominant optic atrophy". Investigative Ophthalmology & Visual Science 43 (6): 1715–24. PMID 12036970.
  • Aung T, Ocaka L, Ebenezer ND, Morris AG, Brice G, Child AH et al. (May 2002). "Investigating the association between OPA1 polymorphisms and glaucoma: comparison between normal tension and high tension primary open angle glaucoma". Human Genetics 110 (5): 513–4. doi:10.1007/s00439-002-0711-9. PMID 12073024.
  • Olichon A, Emorine LJ, Descoins E, Pelloquin L, Brichese L, Gas N et al. (Jul 2002). "The human dynamin-related protein OPA1 is anchored to the mitochondrial inner membrane facing the inter-membrane space". FEBS Letters 523 (1-3): 171–6. doi:10.1016/S0014-5793(02)02985-X. PMID 12123827.
  • Marchbank NJ, Craig JE, Leek JP, Toohey M, Churchill AJ, Markham AF et al. (Aug 2002). "Deletion of the OPA1 gene in a dominant optic atrophy family: evidence that haploinsufficiency is the cause of disease". Journal of Medical Genetics 39 (8): e47. doi:10.1136/jmg.39.8.e47. PMC 1735190. PMID 12161614.
  • Satoh M, Hamamoto T, Seo N, Kagawa Y, Endo H (Jan 2003). "Differential sublocalization of the dynamin-related protein OPA1 isoforms in mitochondria". Biochemical and Biophysical Research Communications 300 (2): 482–93. doi:10.1016/S0006-291X(02)02874-7. PMID 12504110.
  • Olichon A, Baricault L, Gas N, Guillou E, Valette A, Belenguer P et al. (Mar 2003). "Loss of OPA1 perturbates the mitochondrial inner membrane structure and integrity, leading to cytochrome c release and apoptosis". The Journal of Biological Chemistry 278 (10): 7743–6. doi:10.1074/jbc.C200677200. PMID 12509422.
  • Shimizu S, Mori N, Kishi M, Sugata H, Tsuda A, Kubota N (Feb 2003). "A novel mutation in the OPA1 gene in a Japanese patient with optic atrophy". American Journal of Ophthalmology 135 (2): 256–7. doi:10.1016/S0002-9394(02)01929-3. PMID 12566046.

External links