Differential Epigenetic Status and Responses to Stressors between Retinal Cybrids Cells with African versus European Mitochondrial DNA: Insights into Disease Susceptibilities
Shari R. Atilano,
Sina Abedi,
Narcisa V. Ianopol,
Mithalesh K. Singh,
J Lucas Norman,
Deepika Malik,
Payam Falatoonzadeh,
Marilyn Chwa,
Anthony B. Nesburn,
Baruch D. Kuppermann,
M. Cristina Kenney
Affiliations
Shari R. Atilano
Gavin Herbert Eye Institute, Ophthalmology Research Laboratory, University of California Irvine, Hewitt Hall, Room 2028, 843 Health Science Rd., Irvine, CA 92697, USA
Sina Abedi
Gavin Herbert Eye Institute, Ophthalmology Research Laboratory, University of California Irvine, Hewitt Hall, Room 2028, 843 Health Science Rd., Irvine, CA 92697, USA
Narcisa V. Ianopol
Gavin Herbert Eye Institute, Ophthalmology Research Laboratory, University of California Irvine, Hewitt Hall, Room 2028, 843 Health Science Rd., Irvine, CA 92697, USA
Mithalesh K. Singh
Gavin Herbert Eye Institute, Ophthalmology Research Laboratory, University of California Irvine, Hewitt Hall, Room 2028, 843 Health Science Rd., Irvine, CA 92697, USA
J Lucas Norman
Gavin Herbert Eye Institute, Ophthalmology Research Laboratory, University of California Irvine, Hewitt Hall, Room 2028, 843 Health Science Rd., Irvine, CA 92697, USA
Deepika Malik
Gavin Herbert Eye Institute, Ophthalmology Research Laboratory, University of California Irvine, Hewitt Hall, Room 2028, 843 Health Science Rd., Irvine, CA 92697, USA
Payam Falatoonzadeh
Gavin Herbert Eye Institute, Ophthalmology Research Laboratory, University of California Irvine, Hewitt Hall, Room 2028, 843 Health Science Rd., Irvine, CA 92697, USA
Marilyn Chwa
Gavin Herbert Eye Institute, Ophthalmology Research Laboratory, University of California Irvine, Hewitt Hall, Room 2028, 843 Health Science Rd., Irvine, CA 92697, USA
Anthony B. Nesburn
Gavin Herbert Eye Institute, Ophthalmology Research Laboratory, University of California Irvine, Hewitt Hall, Room 2028, 843 Health Science Rd., Irvine, CA 92697, USA
Baruch D. Kuppermann
Gavin Herbert Eye Institute, Ophthalmology Research Laboratory, University of California Irvine, Hewitt Hall, Room 2028, 843 Health Science Rd., Irvine, CA 92697, USA
M. Cristina Kenney
Gavin Herbert Eye Institute, Ophthalmology Research Laboratory, University of California Irvine, Hewitt Hall, Room 2028, 843 Health Science Rd., Irvine, CA 92697, USA
Mitochondrial (mt) DNA can be classified into haplogroups, which represent populations with different geographic origins. Individuals of maternal African backgrounds (L haplogroup) are more prone to develop specific diseases compared those with maternal European-H haplogroups. Using a cybrid model, effects of amyloid-β (Amyβ), sub-lethal ultraviolet (UV) radiation, and 5-Aza-2′-deoxycytidine (5-aza-dC), a methylation inhibitor, were investigated. Amyβ treatment decreased cell metabolism and increased levels of reactive oxygen species in European-H and African-L cybrids, but lower mitochondrial membrane potential (ΔΨM) was found only in African-L cybrids. Sub-lethal UV radiation induced higher expression levels of CFH, EFEMP1, BBC3, and BCL2L13 in European-H cybrids compared to African-L cybrids. With respect to epigenetic status, the African-L cybrids had (a) 4.7-fold higher total global methylation levels (p = 0.005); (b) lower expression patterns for DNMT3B; and (c) elevated levels for HIST1H3F. The European-H and African-L cybrids showed different transcription levels for CFH, EFEMP1, CXCL1, CXCL8, USP25, and VEGF after treatment with 5-aza-dC. In conclusion, compared to European-H haplogroup cybrids, the African-L cybrids have different (i) responses to exogenous stressors (Amyβ and UV radiation), (ii) epigenetic status, and (iii) modulation profiles of methylation-mediated downstream complement, inflammation, and angiogenesis genes, commonly associated with various human diseases.
