OPA1 and Its Clinical Implications

Eva Trevisson, University of Padova, Padua, Italy
Leonardo Salviati, University of Padova, Padua, Italy
Luca Scorrano, University of Geneva, Geneva, Switzerland

Published online: December 2009

DOI: 10.1002/9780470015902.a0021785

Autosomal dominant optic atrophy (ADOA) or Kjer disease (MIM #) is a primary inherited nonsyndromic optic neuropathy that results in loss of retinal ganglion cells, leading to the clinical appearance of optic atrophy. It is caused by mutations in optic atrophy 1 (OPA1), a dynamin-related protein of the inner mitochondrial membrane. Recent evidence supports a role for OPA1 in the regulation of the process of cristae remodelling during apoptosis, by which the complete release of mitochondrial stores of cytochrome c is achieved, supporting a role for apoptosis in the pathogenesis of ADOA. Here we review the basic clinical features of ADOA, the biology of OPA1 and its role in the regulation of mitochondrial shape changes during apoptosis.

Key concepts

  • Mitochondrial shape changes during apoptosis.
  • Cristae are the main store of cytochrome c.
  • The complete release of cytochrome c is accompanied by the remodelling of the cristae.
  • The dynamin-related protein OPA1 regulates the shape of the cristae.
  • Dis-oligomerization of OPA1 is a key event in the release of cytochrome c during apoptosis.

Keywords: mitochondria; apoptosis; fusion; fission; cristae remodelling; cytochrome c release

Figure 1. A cartoon depicting the OPA1-containing oligomer at the cristae junction. The cristae is represented as the fold of the inner mitochondrial membrane (IMM). The soluble and membrane bound OPA1 forms interact to form an oligomer. The specified Flag and His tag refer to the (Frezza et al., 2006) paper in which tagged forms were employed to verify the composition of the OPA1 oligomer.
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 References
    Alexander C, Votruba M, Pesch UE et al. (2000) OPA1, encoding a dynamin-related GTPase, is mutated in autosomal dominant optic atrophy linked to chromosome 3q28. Nature Genetics 26: 211–215.
    Bach D, Pich S, Soriano FX et al. (2003) Mitofusin-2 determines mitochondrial network architecture and mitochondrial metabolism. A novel regulatory mechanism altered in obesity. Journal of Biological Chemistry 278: 17190–17197.
    Bernardi P and Azzone GF (1981) Cytochrome c as an electron shuttle between the outer and inner mitochondrial membranes. Journal of Biological Chemistry 256: 7187–7192.
    de Brito OM and Scorrano L (2008a) Mitofusin 2: a mitochondria-shaping protein with signaling roles beyond fusion. Antioxidants & Redox Signaling 10: 621–633.
    de Brito OM and Scorrano L (2008b) Mitofusin 2 tethers endoplasmic reticulum to mitochondria. Nature 456: 605–610.
    Cereghetti GM, Stangherlin A, Martins de BO et al. (2008) Dephosphorylation by calcineurin regulates translocation of Drp1 to mitochondria. Proceedings of the National Academy of Sciences of the USA 105: 15803–15808.
    Chang CR and Blackstone C (2007) Cyclic AMP-dependent protein kinase phosphorylation of Drp1 regulates its GTPase activity and mitochondrial morphology. The Journal of Biological Chemistry 282: 21583–21587.
    Chen H, Detmer SA, Ewald AJ et al. (2003) Mitofusins Mfn1 and Mfn2 coordinately regulate mitochondrial fusion and are essential for embryonic development. Journal of Cell Biology 160: 189–200.
    Chen H, McCaffery JM and Chan DC (2007) Mitochondrial fusion protects against neurodegeneration in the cerebellum. Cell 130: 548–562.
    Chen KH, Guo X, Ma D et al. (2004) Dysregulation of HSG triggers vascular proliferative disorders. Nature Cell Biology 6: 872–883.
    Cipolat S, de Brito OM, Dal Zilio B and Scorrano L (2004) OPA1 requires mitofusin 1 to promote mitochondrial fusion. Proceedings of the National Academy of Sciences of the USA 101: 15927–15932.
    Cipolat S, Rudka T, Hartmann D et al. (2006) Mitochondrial rhomboid PARL regulates cytochrome c release during apoptosis via opa1-dependent cristae remodeling. Cell 126: 163–175.
    Collins TJ, Berridge MJ, Lipp P and Bootman MD (2002) Mitochondria are morphologically and functionally heterogeneous within cells. EMBO Journal 21: 1616–1627.
    Cribbs JT and Strack S (2007) Reversible phosphorylation of Drp1 by cyclic AMP-dependent protein kinase and calcineurin regulates mitochondrial fission and cell death. EMBO Reports 8: 939–944.
    Danial NN and Korsmeyer SJ (2004) Cell death: critical control points. Cell 116: 205–219.
    Danino D and Hinshaw JE (2001) Dynamin family of mechanoenzymes. Current Opinion in Cell Biology 13: 454–460.
    Davies VJ, Hollins AJ, Piechota MJ et al. (2007) Opa1 deficiency in a mouse model of autosomal dominant optic atrophy impairs mitochondrial morphology, optic nerve structure and visual function. Human Molecular Genetics 16: 1307–1318.
    Delettre C, Griffoin JM, Kaplan J et al. (2001) Mutation spectrum and splicing variants in the OPA1 gene. Human Genetics 109: 584–591.
    Delettre C, Lenaers G, Griffoin JM et al. (2000) Nuclear gene OPA1, encoding a mitochondrial dynamin-related protein, is mutated in dominant optic atrophy. Nature Genetics 26: 207–210.
    Dimmer KS and Scorrano L (2006) (De)constructing mitochondria: what for? Physiology (Bethesda) 21: 233–241.
    Dimmer KS, Fritz S, Fuchs F et al. (2002) Genetic basis of mitochondrial function and morphology in Saccharomyces cerevisiae. Molecular Biology of the Cell 13: 847–853.
    Ferre M, Amati-Bonneau P, Tourmen Y, Malthiery Y and Reynier P (2005) eOPA1: an online database for OPA1 mutations. Human Mutation 25: 423–428.
    Frey TG and Mannella CA (2000) The internal structure of mitochondria. Trends in Biochemical Sciences 25: 319–324.
    Frezza C, Cipolat S, Martins dB et al. (2006) OPA1 controls apoptotic cristae remodeling independently from mitochondrial fusion. Cell 126: 177–189.
    Fuhrmann N, Alavi MV, Bitoun P et al. (2009) Genomic rearrangements in OPA1 are frequent in patients with autosomal dominant optic atrophy. Journal of Medical Genetics 46: 136–144.
    Harder Z, Zunino R and McBride H (2004) Sumo1 conjugates mitochondrial substrates and participates in mitochondrial fission. Current Biology 14: 340–345.
    Ishihara N, Eura Y and Mihara K (2004) Mitofusin 1 and 2 play distinct roles in mitochondrial fusion reactions via GTPase activity. Journal of Cell Science 117: 6535–6546.
    Johnston PB, Gaster RN, Smith VC and Tripathi RC (1979) A clinicopathologic study of autosomal dominant optic atrophy. American Journal of Ophthalmology 88: 868–875.
    Kjer B, Eiberg H, Kjer P and Rosenberg T (1996) Dominant optic atrophy mapped to chromosome 3q region. II. Clinical and epidemiological aspects. Acta Ophthalmologica Scandinavica 74: 3–7.
    Koshiba T, Detmer SA, Kaiser JT et al. (2004) Structural basis of mitochondrial tethering by mitofusin complexes. Science 305: 858–862.
    Okamoto K and Shaw JM (2005) Mitochondrial morphology and dynamics in yeast and multicellular eukaryotes. Annual Review of Genetics 39: 503–536.
    Olichon A, Elachouri G, Baricault L et al. (2007) OPA1 alternate splicing uncouples an evolutionary conserved function in mitochondrial fusion from a vertebrate restricted function in apoptosis. Cell Death and Differentiation 14: 682–692.
    Palade GE (1952) The fine structure of mitochondria. Anatomical Record: Advances in Integrative Anatomy and Evolutionary Biology 114: 427–451.
    Pelloquin L, Belenguer P, Menon Y, Gas N and Ducommun B (1999) Fission yeast Msp1 is a mitochondrial dynamin-related protein. Journal of Cell Science 112: 4151–4161.
    Pesch UE, Leo-Kottler B, Mayer S et al. (2001) OPA1 mutations in patients with autosomal dominant optic atrophy and evidence for semi-dominant inheritance. Human Molecular Genetics 10: 1359–1368.
    Pitts KR, Yoon Y, Krueger EW and McNiven MA (1999) The dynamin-like protein DLP1 is essential for normal distribution and morphology of the endoplasmic reticulum and mitochondria in mammalian cells. Molecular Biology of the Cell 10: 4403–4417.
    Praefcke GJ and McMahon HT (2004) The dynamin superfamily: universal membrane tubulation and fission molecules? Nature Reviews Molecular Cell Biology 5: 133–147.
    Rojo M, Legros F, Chateau D and Lombes A (2002) Membrane topology and mitochondrial targeting of mitofusins, ubiquitous mammalian homologs of the transmembrane GTPase Fzo. Journal of Cell Science 115: 1663–1674.
    Scorrano L, Ashiya M, Buttle K et al. (2002) A distinct pathway remodels mitochondrial cristae and mobilizes cytochrome c during apoptosis. Developmental Cell 2: 55–67.
    Suen DF, Norris KL and Youle RJ (2008) Mitochondrial dynamics and apoptosis. Genes & Development 22: 1577–1590.
    Suzuki M, Jeong SY, Karbowski M, Youle RJ and Tjandra N (2003) The solution structure of human mitochondria fission protein Fis1 reveals a novel TPR-like helix bundle. Journal of Molecular Biology 334: 445–458.
    Taguchi N, Ishihara N, Jofuku A, Oka T and Mihara K (2007) Mitotic phosphorylation of dynamin-related GTPase Drp1 participates in mitochondrial fission. Journal of Biological Chemistry 282: 11521–11529.
    Thiselton DL, Alexander C, Morris A et al. (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: 498–502.
    Toomes C, Marchbank NJ, Mackey DA et al. (2001) Spectrum, frequency and penetrance of OPA1 mutations in dominant optic atrophy. Human Molecular Genetics 10: 1369–1378.
    Twig G, Graf SA, Wikstrom JD et al. (2006) Tagging and tracking individual networks within a complex mitochondrial web with photoactivatable GFP. American Journal of Physiology Cell Physiology 291: C176–C184.
    Votruba M, Moore AT and Bhattacharya SS (1998) Clinical features, molecular genetics, and pathophysiology of dominant optic atrophy. Journal of Medical Genetics 35: 793–800.
    Wasiak S, Zunino R and McBride HM (2007) Bax/Bak promote sumoylation of DRP1 and its stable association with mitochondria during apoptotic cell death. Journal of Cell Biology 177: 439–450.
    Wong ED, Wagner JA, Gorsich SW et al. (2000) The dynamin-related GTPase, Mgm1p, is an intermembrane space protein required for maintenance of fusion competent mitochondria. Journal of Cell Biology 151: 341–352.
    Yamaguchi R, Lartigue L, Perkins G et al. (2008) Opa1-mediated cristae opening is Bax/Bak and BH3 dependent, required for apoptosis, and independent of Bak oligomerization. Molecular Cell 31: 557–569.
    Yoon Y, Krueger EW, Oswald BJ and McNiven MA (2003) The mitochondrial protein hFis1 regulates mitochondrial fission in mammalian cells through an interaction with the dynamin-like protein DLP1. Molecular & Cellular Biology 23: 5409–5420.
    Yoon Y, Pitts KR, Dahan S and McNiven MA (1998) A novel dynamin-like protein associates with cytoplasmic vesicles and tubules of the endoplasmic reticulum in mammalian cells. Journal of Cell Biology 140: 779–793.
    Zuchner S, Mersiyanova IV, Muglia M et al. (2004) Mutations in the mitochondrial GTPase mitofusin 2 cause Charcot-Marie-Tooth neuropathy type 2A. Nature Genetics 36: 449–451.
 Further Reading
    Amati-Bonneau P, Valentino ML, Reynier P et al. (2008) OPA1 mutations induce mitochondrial DNA instability and optic atrophy ‘plus’ phenotypes. Brain 131: 338–351.
    Cereghetti GM and Scorrano L (2006) The many shapes of mitochondrial death. Oncogene 25: 4717–4724.
    Scorrano L and Korsmeyer SJ (2003) Mechanisms of cytochrome c release by proapoptotic BCL-2 family members. Biochemical and Biophysical Research Communications 304: 437–444.
    Spinazzi M, Cazzola S, Bortolozzi M et al. (2008) A novel deletion in the GTPase domain of OPA1 causes defects in mitochondrial morphology and distribution, but not in function. Human Molecular Genetics 17: 3291–3302.

Related Sub-Topics:

Neurobiology of Disease | Sensory Systems | Neurons | Specific Genetic Disorders | Mitochondrial Diseases | Mechanisms of Cell Death, Senescence and Metabolism
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Article Title: OPA1 and Its Clinical Implications
 
How to Cite close
Trevisson, Eva, Salviati, Leonardo, and Scorrano, Luca(Dec 2009) OPA1 and Its Clinical Implications. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0021785]