June 2013
Volume 54, Issue 15
Free
ARVO Annual Meeting Abstract  |   June 2013
An In-Vitro Study of Wnt Pathway Modulation in Cybrid H and J Mitochondrial Haplogroups and the Possible Implications for Age-related Macular Degeneration
Author Affiliations & Notes
  • Payam Falatoonzadeh
    Ophthalmology, Gavin Herbert Eye Inst., UC Irvine, Irvine, CA
  • Grace Woo
    Ophthalmology, Gavin Herbert Eye Inst., UC Irvine, Irvine, CA
  • Nitin Udar
    Ophthalmology, Gavin Herbert Eye Inst., UC Irvine, Irvine, CA
  • Shari Atilano
    Ophthalmology, Gavin Herbert Eye Inst., UC Irvine, Irvine, CA
  • Marilyn Chwa
    Ophthalmology, Gavin Herbert Eye Inst., UC Irvine, Irvine, CA
  • Miceli Michael
    Tulane Center for Aging, Tulane University, New Orleans, LA
  • S Michal Jazwinski
    Tulane Center for Aging, Tulane University, New Orleans, LA
  • Cristina Kenney
    Ophthalmology, Gavin Herbert Eye Inst., UC Irvine, Irvine, CA
  • Footnotes
    Commercial Relationships Payam Falatoonzadeh, None; Grace Woo, None; Nitin Udar, Illumina (E); Shari Atilano, None; Marilyn Chwa, None; Miceli Michael, None; S Michal Jazwinski, None; Cristina Kenney, None
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science June 2013, Vol.54, 4998. doi:https://doi.org/
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      Payam Falatoonzadeh, Grace Woo, Nitin Udar, Shari Atilano, Marilyn Chwa, Miceli Michael, S Michal Jazwinski, Cristina Kenney; An In-Vitro Study of Wnt Pathway Modulation in Cybrid H and J Mitochondrial Haplogroups and the Possible Implications for Age-related Macular Degeneration. Invest. Ophthalmol. Vis. Sci. 2013;54(15):4998. doi: https://doi.org/.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract
 
Purpose
 

The wet form of age-related macular degeneration (AMD) can be associated with increased VEGF, vascular cell proliferation, and induced choroidal neovascularization. Mitochondrial DNA (mtDNA) haplogroups are defined by accumulation of SNPs that represent different geographic origins of populations. Individuals with haplogroup H mtDNA are lower risk for AMD, while haplogroup J individuals have higher predisposition. The Wnt pathway and β-Catenin, one of its downstream proteins, are commonly associated with cell proliferation, and studies have focused on its role in angiogenesis related to cancer and possibly AMD. Our present study uses a mitochondrial haplogroup cytoplasmic hybrid (cybrid) model to assess the effects of mtDNA variations on the Wnt pathway.

 
Methods
 

Mitochondria-deficient (Rho0) human ARPE-19 cells were fused with platelets from individuals with mtDNA haplogroups H (n=3) or J (n=3) to establish cybrid cell lines. RNA was extracted from each cybrid and cDNA synthesized. Q-PCR was performed using primers for various genes associated with the Wnt pathway and analyzed for changes in gene expression levels of J cybrids relative to H cybrids.

 
Results
 

Gene expression levels were significantly decreased in J cybrids relative to H cybrids for inhibitors of the Wnt pathway, including SFRP1 (0.29 fold, p=0.0001), DKK3 (0.46 fold, p=0.004), and RARA1 (0.57 fold, p=0.007). There was also a relative increase in expression of GSK3 (1.6 fold, p=0.005). Expression levels of other members of the Wnt pathway, including CSNK1E, WNT9A, LRP1, KREMEN1, MDM2, and TGFβ were not found to be significantly different in the J versus the H cybrids.

 
Conclusions
 

SFRP1 and DKK3 inhibit the binding and interaction of the Wnt ligand with cell surface receptors. Decreased expression of these genes in J cybrids could potentially lead to more Wnt ligand binding and increased signal transduction within the cell. This would include recruitment of increased GSK3A away from the β-catenin degradation complex. Also, decreased RARA1 levels, a nuclear inhibitor of β-catenin, would allow for more β-catenin driven transcription. These observations correlate with faster cybrid J growth patterns in culture, and may also have implications for how different haplogroups might modulate the Wnt pathway and possibly influence AMD.

 
Keywords: 600 mitochondria • 412 age-related macular degeneration • 701 retinal pigment epithelium  
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