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VOLUME 16 , ISSUE 3 ( September-December, 2022 ) > List of Articles


Mitochondrial Genome Alterations, Cytochrome C Oxidase Activity, and Oxidative Stress: Implications in Primary Open-angle Glaucoma

Kuldeep Mohanty, Swetasmita Mishra, Rima Dada, Tanuj Dada

Keywords : Case-control study, Cytochrome C oxidase, Mitochondrial genome alterations, Oxidative stress, Primary open-angle glaucoma

Citation Information : Mohanty K, Mishra S, Dada R, Dada T. Mitochondrial Genome Alterations, Cytochrome C Oxidase Activity, and Oxidative Stress: Implications in Primary Open-angle Glaucoma. J Curr Glaucoma Pract 2022; 16 (3):158-165.

DOI: 10.5005/jp-journals-10078-1376

License: CC BY-NC 4.0

Published Online: 23-01-2023

Copyright Statement:  Copyright © 2022; The Author(s).


Aim: To evaluate mitochondrial genome alterations, cytochrome C oxidase (COX) activity, and oxidative stress in primary open-angle glaucoma (POAG). Methodology: Whole mitochondrial genome was screened in 75 POAG cases and 105 controls by polymerase chain reaction (PCR) sequencing. COX activity was measured from peripheral blood mononuclear cells (PBMCs). A protein modeling study was done to evaluate the impact of G222E variant on protein function. Levels of 8-hydroxy-2-deoxyguanosine (8-OHdG), 8-isoprostane (8-IP), and total antioxidant capacity (TAC) were also measured. Results: A total of 156 and 79 mitochondrial nucleotide variations were found in the cohort of 75 POAG patients and 105 controls, respectively. Ninety-four (60.26%) variations spanned the coding region, and 62 (39.74%) variations spanned noncoding regions (D-loop, 12SrRNA, and 16SrRNA) of mitochondrial genome in POAG patients. Out of 94 nucleotide changes in coding region, 68 (72.34%) were synonymous changes, 23 (24.46%) non-synonymous, and three (3.19%) were found in the region coding for transfer ribonucleic acid (tRNA). Three changes (p.E192K in ND1, p.L128Q in ND2, and p.G222E in COX2) were found to be pathogenic. Twenty-four (32.0%) patients were positive for either of these pathogenic mitochondrial deoxyribonucleic acid (mtDNA) nucleotide changes. Majority of cases (18.7%) had pathogenic mutation in COX2 gene. Patients who harbored pathogenic mtDNA change in COX2 gene had significantly lower levels of COX activity (p < 0.0001) and TAC (p = 0.004), and higher levels of 8-IP (p = 0.01) as compared to patients who did not harbor this mtDNA. G222E changed the electrostatic potential and adversely impacted protein function of COX2 by affecting nonpolar interactions with neighboring subunits. Conclusion: Pathogenic mtDNA mutations were present in POAG patients, which were associated with reduced COX activity and increased levels of oxidative stress. Clinical significance: POAG patients should be evaluated for mitochondrial mutations and oxidative stress and may be managed accordingly with antioxidant therapies.

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  1. Abu-Amero K, Kondkar AA, Chalam KV. An updated review on the genetics of primary open angle glaucoma. Int J Mol Sci 2015;16(12):28886–288911. DOI: 10.3390/ijms161226135
  2. Allingham RR, Liu Y, Rhee DJ. The genetics of primary open-angle glaucoma: a review. Exp Eye Res 2009;88(4):837–844. DOI: 10.1016/j.exer.2008.11.003
  3. Greenberg BD, Newbold JE, Sugino A. Intraspecific nucleotide sequence variability surrounding the origin of replication in human mitochondrial DNA. Gene 1983;21(1-2):33–49. DOI: 10.1016/0378-1119(83)90145-2
  4. Chinnery PF, Howell N, Andrews RM, et al. Clinical mitochondrial genetics. J Med Genet 1999;36(6):425–436.
  5. Taylor RW, Pyle A, Griffin H, et al. Use of whole-exome sequencing to determine the genetic basis of multiple mitochondrial respiratory chain complex deficiencies.JAMA 2014;312(1):68–77. DOI: 10.1001/jama.2014.7184
  6. Osborne NN, Kamalden TA, Majid ASA, et al. Light effects on mitochondrial photosensitizers in relation to retinal degeneration. Neurochem Res 2010;35(12):2027–2034. DOI: 10.1007/s11064-010-0273-5
  7. Lee S, Sheck L, Crowston JG, et al. Impaired complex-I-linked respiration and ATP synthesis in primary open-angle glaucoma patient lymphoblasts. Invest Ophthalmol Vis Sci 2012;53(4):2431–2437. DOI: 10.1167/iovs.12-9596
  8. Kumar M, Kaur P, Kumar M, et al. Clinical characterization and mitochondrial DNA sequence variations in Leber hereditary optic neuropathy. Mol Vis 2012;18:2687–2699.
  9. Kumar M, Tanwar M, Faiq MA, et al. Mitochondrial DNA nucleotide changes in primary congenital glaucoma patients. Mol Vis 2013;19:220–230.
  10. Zhou X, Liu R, Wu Z. Recent progress in research on oxidative stress in glaucoma. Zhonghua Yan Ke Za Zhi 2014;50(8):634–637.
  11. Lin WJ, Kuang HY. Oxidative stress induces autophagy in response to multiple noxious stimuli in retinal ganglion cells. Autophagy 2014;10(10):1692–1701. DOI: 10.4161/auto.36076
  12. Lopez-Riquelme N, Villalba C, Tormo C, et al. Endothelin-1 levels and biomarkers of oxidative stress in glaucoma patients. Int Ophthalmol 2015;35(4):527–532. DOI: 10.1007/s10792-014-9979-8
  13. Tanwar M, Dada T, Sihota R, et al. Mitochondrial DNA analysis in primary congenital glaucoma. Mol Vis 2010;16:518–533.
  14. Hodapp E, Parrish R, Anderson DR. Clinical Decisions in Glaucoma. St. Louis: C. V. Mosby; 1993.
  15. Sambrook J, Fritsch EF. Molecular Cloning: A Laboratory Manual. 2nd ed. Cold Spring Harbor Press; 1989.
  16. Karabatsiakis A, Böck C, Salinas-Manrique J, et al. Mitochondrial respiration in peripheral blood mononuclear cells correlates with depressive subsymptoms and severity of major depression. Transl Psychiatry 2014;4(6):e397. DOI: 10.1038/tp.2014.44
  17. Berman HM, Westbrook J, Feng Z, et al. The protein data bank. Nucleic Acids Res 2000;28(1):235–242. DOI: 10.1093/nar/28.1.235
  18. Tsukihara T, Shimokata K, Katayama Y, et al. The low-spin heme of cytochrome c oxidase as the driving element of the proton-pumping process. Proc Natl Acad Sci U S A 2003;100(26):15304–15309. DOI: 10.1073/pnas.2635097100
  19. Sali A, Blundell TL. Comparative protein modelling by satisfaction of spatial restraints. J Mol Biol 1993;234(3):779–815. DOI: 10.1006/jmbi.1993.1626
  20. Shen MY, Sali A. Statistical potential for assessment and prediction of protein structures. Protein Sci 2006;15(11):2507–2524. DOI: 10.1110/ps.062416606
  21. Discovery Studio 2.0 [Accelrys Software Inc]. San Diego, CA, USA: Molecular Modeling Program Package; 2006.
  22. Laskowski RA, MacArthur MW, Moss DS, et al. PROCHECK: a program to check the steriochemical quality of protein structures. J Appl Crystallogr 1993;26(2):283–291. DOI: 10.1107/S0021889892009944
  23. Baradaran R, Berrisford JM, Minhas GS, et al. Crystal structure of the entire respiratory complex I. Nature 2013;494(7438):443–448. DOI: 10.1038/nature11871
  24. Efremov RG, Baradaran R, Sazanov LA, et al. The architecture of respiratory complex I. Nature 2010;465(7297):441–445. DOI: 10.1038/nature09066
  25. Yu-Wai-Man P, Griffiths PG, Hudson G, et al. Inherited mitochondrial optic neuropathies. J Med Genet 2009;46(3):145–158. DOI: 10.1136/jmg.2007.054270
  26. Mathiesen C, Hagerhall C. Transmembrane topology of the NuoL, M and N subunits of NADH: quinone oxidoreductase and their homologues among membrane bound hydrogenases and bona fide antiporters. BiochimBiophys Acta 2002;1556(2-3):121–132. DOI: 10.1016/s0005-2728(02)00343-2
  27. Gong X, Xie T, Yu L, et al. The ubiquinone-binding site in NADH:ubiquinone oxidoreductase from Escherichia coli. J Biol Chem 2003;278(28):25731–25737. DOI: 10.1074/jbc.M302361200
  28. Shaughnessy DT, McAllister K, Worth L, et al. Mitochondria, energetics, epigenetics, and cellular responses to stress. Environ Health Perspect 2014;122(12):1271–1278. DOI: 10.1289/ehp.1408418
  29. Santos D, Esteves AR, Silva DF, et al. The impact of mitochondrial fusion and fission modulation in sporadic Parkinson's disease. Mol Neurobiol 2015;52(1):573–586. DOI: 10.1007/s12035-014-8893-4
  30. Picone P, Nuzzo D, Caruana L, et al. Mitochondrial dysfunction: different routes to Alzheimer's disease therapy. Oxid Med Cell Longev 2014;2014:780179. DOI: 10.1155/2014/780179
  31. Chrysostomou V, Rezania F, Trounce IA, et al. Oxidative stress and mitochondrial dysfunction in glaucoma. Curr Opin Pharmacol 2013;13(1):12–15. DOI: 10.1016/j.coph.2012.09.008
  32. Wu JH, Zhang SH, Nickerson JM, et al. Cumulative mtDNA damage and mutations contribute to the progressive loss of RGCs in a rat model of glaucoma. Neurobiol Dis 2015;74:167–179. DOI: 10.1016/j.nbd.2014.11.014
  33. Osborne NN, Alvarez CN, Aguado SDO. Targeting mitochondrial dysfunction as in aging and glaucoma. Drug Discov Today 2014;19(10):1613–1622. DOI: 10.1016/j.drudis.2014.05.010
  34. Kumar M, Tanwar M, Saxena R, et al. Identification of novel mitochondrial mutations in Leber's hereditary optic neuropathy. Mol Vis 2010;16:782–792.
  35. Banerjee D, Banerjee A, Mookherjee S, et al. Mitochondrial genome analysis of primary open angle glaucoma patients. PLoS One 2013;8(8):e70760. DOI: 10.1371/journal.pone.0070760
  36. Khawaja AP, Bailey JNC, Kang JH, et al. Assessing the association of mitochondrial genetic variation with primary open angle glaucoma using gene-set analyses. Invest Ophthalmol Vis Sci 2016;57(11):5046–5052. DOI: 10.1167/iovs.16-20017
  37. Collins DW, Gudiseva HV, Trachtman B, et al. Association of primary open-angle glaucoma with mitochondrial variants and haplogroups common in African Americans. Mol Vis 2016;16:454–471.
  38. Gudiseva HV, Pistilli M, Salowe R, et al. The association of mitochondrial DNA haplogroups with POAG in African Americans. Exp Eye Res 2019;181:85–89. DOI: 10.1016/j.exer.2019.01.015
  39. He Y, Leung KW, Zhang YH, et al. Mitochondrial complex I defect induces ROS release and degeneration in trabecular meshwork cells of POAG patients: protection by antioxidants. Invest Ophthalmol Vis Sci 2008;49(4):1447–1458. DOI: 10.1167/iovs.07-1361
  40. Sundaresan P, Simpson DA, Sambare C, et al. Whole-mitochondrial genome sequencing in primary open-angle glaucoma using massively parallel sequencing identifies novel and known pathogenic variants. Genet Med 2015;17:279–284. DOI: 10.1038/gim.2014.121
  41. Delbarba A, Abate G, Prandelli C, et al. Mitochondrial alterations in peripheral mononuclear blood cells from Alzheimer's disease and mild cognitive impairment patients.Oxid Med Cell Longev 2016;2016:5923938. DOI: 10.1155/2016/5923938
  42. Gubert C, Stertz L, Pfaffenseller B, et al. Mitochondrial activity and oxidative stress markers in peripheral blood mononuclear cells of patients with bipolar disorder, schizophrenia, and healthy subjects. J Psychiatr Res 2013;47(10):1396–1402. DOI: 10.1016/j.jpsychires.2013.06.018
  43. Mutisya EM, Bowling AC, Beal MF. Cortical cytochrome oxidase activity is reduced in Alzheimer's disease. J Neurochem 1994;63(6):2179–2184. DOI: 10.1046/j.1471-4159.1994.63062179.x
  44. Goyal A, Srivastava A, Sihota R, et al. Evaluation of oxidative stress markers in aqueous humor of primary open angle glaucoma and primary angle closure glaucoma patients. Curr Eye Res 2014;39(8):823–829. DOI: 10.3109/02713683.2011.556299
  45. Tanito M, Kaidzu S, Takai Y, et al. Correlation between systemic oxidative stress and intraocular pressure level. PLoS One 2015;10(7):e0133582. DOI: 10.1371/journal.pone.0133582
  46. Yang JL, Weissman L, Bohr VA, et al. Mitochondrial DNA damage and repair in neurodegenerative disorders. DNA Repair (Amst) 2008;7(7):1110–1120. DOI: 10.1016/j.dnarep.2008.03.012
  47. Dada T, Mittal D, Mohanty K, et al. Mindfulness meditation reduces intraocular pressure, lowers stress biomarkers and modulates gene expression in glaucoma: A randomized controlled trial. J Glaucoma 2018;27(12):1061–1067. DOI: 10.1097/IJG.0000000000001088
  48. Bhasin MK, Dusek JA, Chang BH, et al. Relaxation response induces temporal transcriptome changes in energy metabolism, insulin secretion and inflammatory pathways. PLoS One 2013;8(5):e62817. DOI: 10.1371/journal.pone.0062817
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