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Hum Mol Genet. 2015 Aug 15;24(16):4491-503. doi: 10.1093/hmg/ddv173. Epub 2015 May 10.

Mitochondrial DNA variants can mediate methylation status of inflammation, angiogenesis and signaling genes.

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Gavin Herbert Eye Institute and.
Gavin Herbert Eye Institute and Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Retina-Vitreous Associates Medical Group, Beverly Hills, CA 90211, USA.
Tulane Center for Aging and Department of Medicine, Tulane University, New Orleans, LA 70118, USA and.
Center of Mitochondrial and Epigenomic Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Gavin Herbert Eye Institute and Department of Pathology and Laboratory Medicine, University of California Irvine, Irvine, CA 92697, USA,


Mitochondrial (mt) DNA can be classified into haplogroups representing different geographic and/or racial origins of populations. The H haplogroup is protective against age-related macular degeneration (AMD), while the J haplogroup is high risk for AMD. In the present study, we performed comparison analyses of human retinal cell cybrids, which possess identical nuclei, but mtDNA from subjects with either the H or J haplogroups, and demonstrate differences in total global methylation, and expression patterns for two genes related to acetylation and five genes related to methylation. Analyses revealed that untreated-H and -J cybrids have different expression levels for nuclear genes (CFH, EFEMP1, VEGFA and NFkB2). However, expression levels for these genes become equivalent after treatment with a methylation inhibitor, 5-aza-2'-deoxycytidine. Moreover, sequencing of the entire mtDNA suggests that differences in epigenetic status found in cybrids are likely due to single nucleotide polymorphisms (SNPs) within the haplogroup profiles rather than rare variants or private SNPs. In conclusion, our findings indicate that mtDNA variants can mediate methylation profiles and transcription for inflammation, angiogenesis and various signaling pathways, which are important in several common diseases.

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