6jtg

Structural highlights

Disease

OPA1_HUMAN Autosomal dominant optic atrophy, classic form;Autosomal dominant optic atrophy plus syndrome. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry.

Function

OPA1_HUMAN Dynamin-related GTPase that is essential for normal mitochondrial morphology by regulating the equilibrium between mitochondrial fusion and mitochondrial fission (PubMed:16778770, PubMed:17709429, PubMed:20185555, PubMed:24616225, PubMed:28746876). Coexpression of isoform 1 with shorter alternative products is required for optimal activity in promoting mitochondrial fusion (PubMed:17709429). Binds lipid membranes enriched in negatively charged phospholipids, such as cardiolipin, and promotes membrane tubulation (PubMed:20185555). The intrinsic GTPase activity is low, and is strongly increased by interaction with lipid membranes (PubMed:20185555). Plays a role in remodeling cristae and the release of cytochrome c during apoptosis (By similarity). Proteolytic processing in response to intrinsic apoptotic signals may lead to disassembly of OPA1 oligomers and release of the caspase activator cytochrome C (CYCS) into the mitochondrial intermembrane space (By similarity). Plays a role in mitochondrial genome maintenance (PubMed:20974897, PubMed:18158317).[UniProtKB:P58281]^{[1] [2] [3] [4] [5] [6] [7]} Inactive form produced by cleavage at S1 position by OMA1 following stress conditions that induce loss of mitochondrial membrane potential, leading to negative regulation of mitochondrial fusion.^[8] Isoforms that contain the alternative exon 4b (present in isoform 4 and isoform 5) are required for mitochondrial genome maintenance, possibly by anchoring the mitochondrial nucleoids to the inner mitochondrial membrane.^[9]

References

1. ↑ Ishihara N, Fujita Y, Oka T, Mihara K. Regulation of mitochondrial morphology through proteolytic cleavage of OPA1. EMBO J. 2006 Jul 12;25(13):2966-77. doi: 10.1038/sj.emboj.7601184. Epub 2006 Jun , 15. PMID:16778770 doi:http://dx.doi.org/10.1038/sj.emboj.7601184
2. ↑ Song Z, Chen H, Fiket M, Alexander C, Chan DC. OPA1 processing controls mitochondrial fusion and is regulated by mRNA splicing, membrane potential, and Yme1L. J Cell Biol. 2007 Aug 27;178(5):749-55. doi: 10.1083/jcb.200704110. Epub 2007 Aug, 20. PMID:17709429 doi:http://dx.doi.org/10.1083/jcb.200704110
3. ↑ Amati-Bonneau P, Valentino ML, Reynier P, Gallardo ME, Bornstein B, Boissiere A, Campos Y, Rivera H, de la Aleja JG, Carroccia R, Iommarini L, Labauge P, Figarella-Branger D, Marcorelles P, Furby A, Beauvais K, Letournel F, Liguori R, La Morgia C, Montagna P, Liguori M, Zanna C, Rugolo M, Cossarizza A, Wissinger B, Verny C, Schwarzenbacher R, Martin MA, Arenas J, Ayuso C, Garesse R, Lenaers G, Bonneau D, Carelli V. OPA1 mutations induce mitochondrial DNA instability and optic atrophy 'plus' phenotypes. Brain. 2008 Feb;131(Pt 2):338-51. doi: 10.1093/brain/awm298. Epub 2007 Dec 24. PMID:18158317 doi:http://dx.doi.org/10.1093/brain/awm298
4. ↑ Ban T, Heymann JA, Song Z, Hinshaw JE, Chan DC. OPA1 disease alleles causing dominant optic atrophy have defects in cardiolipin-stimulated GTP hydrolysis and membrane tubulation. Hum Mol Genet. 2010 Jun 1;19(11):2113-22. doi: 10.1093/hmg/ddq088. Epub 2010 Feb , 25. PMID:20185555 doi:http://dx.doi.org/10.1093/hmg/ddq088
5. ↑ Elachouri G, Vidoni S, Zanna C, Pattyn A, Boukhaddaoui H, Gaget K, Yu-Wai-Man P, Gasparre G, Sarzi E, Delettre C, Olichon A, Loiseau D, Reynier P, Chinnery PF, Rotig A, Carelli V, Hamel CP, Rugolo M, Lenaers G. OPA1 links human mitochondrial genome maintenance to mtDNA replication and distribution. Genome Res. 2011 Jan;21(1):12-20. doi: 10.1101/gr.108696.110. Epub 2010 Oct 25. PMID:20974897 doi:http://dx.doi.org/10.1101/gr.108696.110
6. ↑ 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. J Cell Biol. 2014 Mar 17;204(6):919-29. doi: 10.1083/jcb.201308006. Epub 2014 Mar, 10. PMID:24616225 doi:http://dx.doi.org/10.1083/jcb.201308006
7. ↑ Huang G, Massoudi D, Muir AM, Joshi DC, Zhang CL, Chiu SY, Greenspan DS. WBSCR16 Is a Guanine Nucleotide Exchange Factor Important for Mitochondrial Fusion. Cell Rep. 2017 Jul 25;20(4):923-934. doi: 10.1016/j.celrep.2017.06.090. PMID:28746876 doi:http://dx.doi.org/10.1016/j.celrep.2017.06.090
8. ↑ Head B, Griparic L, Amiri M, Gandre-Babbe S, van der Bliek AM. Inducible proteolytic inactivation of OPA1 mediated by the OMA1 protease in mammalian cells. J Cell Biol. 2009 Dec 28;187(7):959-66. doi: 10.1083/jcb.200906083. PMID:20038677 doi:http://dx.doi.org/10.1083/jcb.200906083
9. ↑ Elachouri G, Vidoni S, Zanna C, Pattyn A, Boukhaddaoui H, Gaget K, Yu-Wai-Man P, Gasparre G, Sarzi E, Delettre C, Olichon A, Loiseau D, Reynier P, Chinnery PF, Rotig A, Carelli V, Hamel CP, Rugolo M, Lenaers G. OPA1 links human mitochondrial genome maintenance to mtDNA replication and distribution. Genome Res. 2011 Jan;21(1):12-20. doi: 10.1101/gr.108696.110. Epub 2010 Oct 25. PMID:20974897 doi:http://dx.doi.org/10.1101/gr.108696.110