Dynamin-like 120 kDa protein explained

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]} and small, round mitochondria.^[6] 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] [7]}

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).^[8] 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.^{[4] [9]} 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]} Moreover, stabilization of mitochondrial cristae by OPA1 protects against mitochondrial dysfunction, cytochrome c release, and reactive oxygen species production, thus preventing cell death.^[10] 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 traced to mutations in the GTPase domain of OPA1, leading to sensorineural hearing loss, ataxia, sensorimotor neuropathy, progressive external ophthalmoplegia, and mitochondrial myopathy.^{[3] [7]} 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.^[7]

Interactions

OPA1 has been shown to interact with:

• Adenonucleotide transporters,^[4]
• ATP synthase,^[4]
• CHCHD3,^[4]
• Mitofilin,^[4]
• Prohibitin,^[4]
• SAMM50,^[4] and
• SLC25A.^[4]

See also

• Kjer's optic neuropathy

Further reading

• Olichon A, Guillou E, Delettre C, Landes T, Arnauné-Pelloquin L, Emorine LJ, Mils V, Daloyau M, Hamel C, Amati-Bonneau P, Bonneau D, Reynier P, Lenaers G, Belenguer P. Mitochondrial dynamics and disease, OPA1. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1763. 5–6. 500–9. 2006. 16737747. 10.1016/j.bbamcr.2006.04.003. free.
• Pawlikowska P, Orzechowski A. [Role of transmembrane GTPases in mitochondrial morphology and activity]. Postepy Biochemii. 53. 1. 53–9. 2007. 17718388.
• Nagase T, Ishikawa K, Miyajima N, Tanaka A, Kotani H, Nomura N, Ohara O. 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. Feb 1998. 9628581. 10.1093/dnares/5.1.31. free.
• Johnston RL, Seller MJ, Behnam JT, Burdon MA, Spalton DJ. Dominant optic atrophy. Refining the clinical diagnostic criteria in light of genetic linkage studies. Ophthalmology. 106. 1. 123–8. Jan 1999. 9917792. 10.1016/S0161-6420(99)90013-1.
• Delettre C, Lenaers G, Griffoin JM, Gigarel N, Lorenzo C, Belenguer P, Pelloquin L, Grosgeorge J, Turc-Carel C, Perret E, Astarie-Dequeker C, Lasquellec L, Arnaud B, Ducommun B, Kaplan J, Hamel CP. Nuclear gene OPA1, encoding a mitochondrial dynamin-related protein, is mutated in dominant optic atrophy. Nature Genetics. 26. 2. 207–10. Oct 2000. 11017079. 10.1038/79936. 24514847.
• Alexander C, Votruba M, Pesch UE, Thiselton DL, Mayer S, Moore A, Rodriguez M, Kellner U, Leo-Kottler B, Auburger G, Bhattacharya SS, Wissinger B. OPA1, encoding a dynamin-related GTPase, is mutated in autosomal dominant optic atrophy linked to chromosome 3q28. Nature Genetics. 26. 2. 211–5. Oct 2000. 11017080. 10.1038/79944. 8314863.
• Toomes C, Marchbank NJ, Mackey DA, Craig JE, Newbury-Ecob RA, Bennett CP, Vize CJ, Desai SP, Black GC, Patel N, Teimory M, Markham AF, Inglehearn CF, Churchill AJ. Spectrum, frequency and penetrance of OPA1 mutations in dominant optic atrophy. Human Molecular Genetics. 10. 13. 1369–78. Jun 2001. 11440989. 10.1093/hmg/10.13.1369. free.
• Thiselton DL, Alexander C, Morris A, Brooks S, Rosenberg T, Eiberg H, Kjer B, Kjer P, Bhattacharya SS, Votruba M. 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. Nov 2001. 11735024. 10.1007/s004390100600. 23854938.
• Delettre C, Griffoin JM, Kaplan J, Dollfus H, Lorenz B, Faivre L, Lenaers G, Belenguer P, Hamel CP. Mutation spectrum and splicing variants in the OPA1 gene. Human Genetics. 109. 6. 584–91. Dec 2001. 11810270. 10.1007/s00439-001-0633-y. 19099209.
• Aung T, Ocaka L, Ebenezer ND, Morris AG, Krawczak M, Thiselton DL, Alexander C, Votruba M, Brice G, Child AH, Francis PJ, Hitchings RA, Lehmann OJ, Bhattacharya SS. A major marker for normal tension glaucoma: association with polymorphisms in the OPA1 gene. Human Genetics. 110. 1. 52–6. Jan 2002. 11810296. 10.1007/s00439-001-0645-7. 20733038.
• Misaka T, Miyashita T, Kubo Y. 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. May 2002. 11847212. 10.1074/jbc.M109260200. free.
• Thiselton DL, Alexander C, Taanman JW, Brooks S, Rosenberg T, Eiberg H, Andreasson S, Van Regemorter N, Munier FL, Moore AT, Bhattacharya SS, Votruba M. A comprehensive survey of mutations in the OPA1 gene in patients with autosomal dominant optic atrophy. Investigative Ophthalmology & Visual Science. 43. 6. 1715–24. Jun 2002. 12036970.
• Aung T, Ocaka L, Ebenezer ND, Morris AG, Brice G, Child AH, Hitchings RA, Lehmann OJ, Bhattacharya SS. 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. May 2002. 12073024. 10.1007/s00439-002-0711-9. 13588421.
• Olichon A, Emorine LJ, Descoins E, Pelloquin L, Brichese L, Gas N, Guillou E, Delettre C, Valette A, Hamel CP, Ducommun B, Lenaers G, Belenguer P. 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. Jul 2002. 12123827. 10.1016/S0014-5793(02)02985-X. 45592235. free.
• Marchbank NJ, Craig JE, Leek JP, Toohey M, Churchill AJ, Markham AF, Mackey DA, Toomes C, Inglehearn CF. 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. 47e–47. Aug 2002. 12161614. 1735190. 10.1136/jmg.39.8.e47.
• Satoh M, Hamamoto T, Seo N, Kagawa Y, Endo H. Differential sublocalization of the dynamin-related protein OPA1 isoforms in mitochondria. Biochemical and Biophysical Research Communications. 300. 2. 482–93. Jan 2003. 12504110. 10.1016/S0006-291X(02)02874-7.
• Olichon A, Baricault L, Gas N, Guillou E, Valette A, Belenguer P, Lenaers G. 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. Mar 2003. 12509422. 10.1074/jbc.C200677200. free.
• Shimizu S, Mori N, Kishi M, Sugata H, Tsuda A, Kubota N. A novel mutation in the OPA1 gene in a Japanese patient with optic atrophy. American Journal of Ophthalmology. 135. 2. 256–7. Feb 2003. 12566046. 10.1016/S0002-9394(02)01929-3.
• Alavi. MV. Fuhrmann. N. Dominant optic atrophy, OPA1, and mitochondrial quality control: understanding mitochondrial network dynamics. Molecular Neurodegeneration. 2013 . 8. 32 . 32 . 10.1186/1750-1326-8-32. 24067127. 3856479 . free .

External links

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

Notes and References

1. Votruba M, Moore AT, Bhattacharya SS . 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 . Jan 1998 . 9490303 . 10.1007/s004390050657 . 26060748 .
2. Web site: Entrez Gene: OPA1 optic atrophy 1 (autosomal dominant).
3. Santarelli R, Rossi R, Scimemi P, Cama E, Valentino ML, La Morgia C, Caporali L, Liguori R, Magnavita V, Monteleone A, Biscaro A, Arslan E, Carelli V . OPA1-related auditory neuropathy: site of lesion and outcome of cochlear implantation . Brain . 138 . Pt 3 . 563–76 . Mar 2015 . 25564500 . 10.1093/brain/awu378 . 4339771.
4. Patten DA, Wong J, Khacho M, Soubannier V, Mailloux RJ, Pilon-Larose K, MacLaurin JG, Park DS, McBride HM, Trinkle-Mulcahy L, Harper ME, Germain M, Slack RS . OPA1-dependent cristae modulation is essential for cellular adaptation to metabolic demand . The EMBO Journal . 33 . 22 . 2676–91 . Nov 2014 . 25298396 . 10.15252/embj.201488349 . 4282575.
5. Anand R, Wai T, Baker MJ, Kladt N, Schauss AC, Rugarli E, Langer T . The i-AAA protease YME1L and OMA1 cleave OPA1 to balance mitochondrial fusion and fission . The Journal of Cell Biology . 204 . 6 . 919–29 . Mar 2014 . 24616225 . 10.1083/jcb.201308006 . 3998800.
6. Wiemerslage L, Lee D . Quantification of mitochondrial morphology in neurites of dopaminergic neurons using multiple parameters. . J Neurosci Methods . 2016 . 26777473 . 10.1016/j.jneumeth.2016.01.008 . 4775301 . 262 . 56–65.
7. Carelli V, Musumeci O, Caporali L, Zanna C, La Morgia C, Del Dotto V, Porcelli AM, Rugolo M, Valentino ML, Iommarini L, Maresca A, Barboni P, Carbonelli M, Trombetta C, Valente EM, Patergnani S, Giorgi C, Pinton P, Rizzo G, Tonon C, Lodi R, Avoni P, Liguori R, Baruzzi A, Toscano A, Zeviani M . Syndromic parkinsonism and dementia associated with OPA1 missense mutations . Annals of Neurology . Mar 2015 . 25820230 . 10.1002/ana.24410 . 78 . 1 . 21–38 . 5008165.
8. Fülöp L, Rajki A, Katona D, Szanda G, Spät A . Extramitochondrial OPA1 and adrenocortical function . Molecular and Cellular Endocrinology . 381 . 1–2 . 70–9 . Dec 2013 . 23906536 . 10.1016/j.mce.2013.07.021 . 5657510 .
9. Fülöp L, Szanda G, Enyedi B, Várnai P, Spät A . The effect of OPA1 on mitochondrial Ca²⁺ signaling . PLOS ONE . 6 . 9 . e25199 . 2011 . 21980395 . 10.1371/journal.pone.0025199 . 3182975. free .
10. Varanita T, Soriano ME, Romanello V, Zaglia T, Quintana-Cabrera R, Semenzato M, Menabò R, Costa V, Civiletto G, Pesce P, Viscomi C, Zeviani M, Di Lisa F, Mongillo M, Sandri M, Scorrano L . The OPA1-dependent mitochondrial cristae remodeling pathway controls atrophic, apoptotic, and ischemic tissue damage . Cell Metabolism . 21 . 6 . 834–44 . Jun 2015 . 26039448 . 10.1016/j.cmet.2015.05.007 . 4457892.