June 2017
Volume 58, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2017
Age-related macular degeneration (AMD) mitochondria modulate epigenetic machinery in transmitochondrial ARPE-19 cybrid cells
Author Affiliations & Notes
  • Sonali R Nashine
    Gavin Herbert Eye Institute, University of California Irvine, Irvine, California, United States
    Ophthalmology, University of California Irvine, Irvine, California, United States
  • Stephanie Yiwei Lu
    Gavin Herbert Eye Institute, University of California Irvine, Irvine, California, United States
    VA Medical Center Long Beach Hospital, Long Beach, California, United States
  • Anthony B Nesburn
    Gavin Herbert Eye Institute, University of California Irvine, Irvine, California, United States
    Cedars-Sinai Medical Center, Los Angeles, California, United States
  • Baruch D Kuppermann
    Gavin Herbert Eye Institute, University of California Irvine, Irvine, California, United States
  • Cristina M Kenney
    Gavin Herbert Eye Institute, University of California Irvine, Irvine, California, United States
    Pathology and Laboratory Medicine, University of California Irvine, Irvine, California, United States
  • Footnotes
    Commercial Relationships   Sonali Nashine, None; Stephanie Lu, None; Anthony Nesburn, None; Baruch Kuppermann, Alcon,Allergan, Apellis, Genentech, GSK, Ophthotech, Regeneron (F), Alcon, Allergan, Catalyst, Genentech, Novartis, Ophthotech, Regeneron (C), Allergan, Genentech, Novartis, Regeneron (R); Cristina Kenney, None
  • Footnotes
    Support  Sonali R. Nashine holds the Arnold and Mabel Beckman Postdoctoral Fellowship; Beckman Initiative for Macular Reserch, Discovery Eye Foundation, RPB foundation, ICTS, Guenther Foundation, Polly and Michael Smith Foundation, Max Factor Family Foundation, Iris and B. Gerald Cantor Foundation, UCI School of Medicine
Investigative Ophthalmology & Visual Science June 2017, Vol.58, 612. doi:
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    • Get Citation

      Sonali R Nashine, Stephanie Yiwei Lu, Anthony B Nesburn, Baruch D Kuppermann, Cristina M Kenney; Age-related macular degeneration (AMD) mitochondria modulate epigenetic machinery in transmitochondrial ARPE-19 cybrid cells. Invest. Ophthalmol. Vis. Sci. 2017;58(8):612.

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

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Abstract

Purpose : Epigenetic changes are known to contribute to the pathogenesis of age-related macular degeneration (AMD). However, the role of AMD mitochondria in mediating those changes has not yet been demonstrated. Therefore the goal of our study was to demonstrate that mitochondria from AMD patients modulate epigenetics in ARPE-19 transmitochondrial cybrids.

Methods : To prepare AMD and normal (NL) ARPE-19 transmitochondrial cybrids (cytoplasmic hybrids), we fused blood platelets obtained from AMD patients and age-matched NL subjects, with Rho0 (lacking mtDNA) human ARPE-19 cells. All cybrids had identical nuclei but differed in mtDNA content. Passage 5 AMD and NL cybrids (n=4) were cultured for 72 hr, RNA was extracted, reverse transcribed to cDNA, and qRT-PCR was performed. Using qRT-PCR, we compared the expression of methylation genes (DNMT1, DNMT3A, DNMT3B, MAT2B, MBD2) and histone deacetylase genes (HDAC1, HDAC6) between NL and AMD cybrids. Student’s t-test was used to measure statistical differences.

Results : We observed that methylation and acetylation genes’ expression were significantly altered between NL and AMD cybrids. DNMT1 gene, which encodes an enzyme that predominantly methylates CpG residues, and MBD2 that represses transcription from methylated gene promoters, were significantly down-regulated (DNMT1: Fold Change (FC)=0.69, P=0.03; MBD2: FC=0.8, P=0.02) in AMD cybrids compared to NL cybrids. Furthermore, DNMT3A and DNMT3B which function as de novo methyltransferases as well as transcriptional repressors, showed significantly increased gene expression (DNMT3A: FC=1.5, P=0.01, DNMT3B: FC=1.5, P=0.008) in AMD cybrids. MAT2B which catalyzes the biosynthesis of S-adenosylmethionine from methionine and ATP, was significantly up-regulated (FC=1.3, P=0.04) in AMD cybrids. In addition, histone deacetylases, HDAC1 and HDAC6, which are responsible for the deacetylation of lysine residues on core histones, were significantly up-regulated (HDAC1: FC=1.5, P=0.0004; HDAC6: FC=2.63, P<0.0001) in AMD cybrids compared to NL cybrids.

Conclusions : To conclude, since all cybrids differed only in mtDNA content, our results suggest that AMD mitochondria can mediate changes in the methylation and acetylation genes’ expression, and regulate the epigenetic machinery in ARPE-19 transmitochondrial cybrids.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.

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