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Hum Mol Genet. 2014 Jul 1;23(13):3537-51. doi: 10.1093/hmg/ddu065. Epub 2014 Feb 28.

Inherited mitochondrial DNA variants can affect complement, inflammation and apoptosis pathways: insights into mitochondrial-nuclear interactions.

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


Age-related macular degeneration (AMD) is the leading cause of vision loss in developed countries. While linked to genetic polymorphisms in the complement pathway, there are many individuals with high risk alleles that do not develop AMD, suggesting that other 'modifiers' may be involved. Mitochondrial (mt) haplogroups, defined by accumulations of specific mtDNA single nucleotide polymorphisms (SNPs) which represent population origins, may be one such modifier. J haplogroup has been associated with high risk for AMD while the H haplogroup is protective. It has been difficult to assign biological consequences for haplogroups so we created human ARPE-19 cybrids (cytoplasmic hybrids), which have identical nuclei but mitochondria of either J or H haplogroups, to investigate their effects upon bioenergetics and molecular pathways. J cybrids have altered bioenergetic profiles compared with H cybrids. Q-PCR analyses show significantly lower expression levels for seven respiratory complex genes encoded by mtDNA. J and H cybrids have significantly altered expression of eight nuclear genes of the alternative complement, inflammation and apoptosis pathways. Sequencing of the entire mtDNA was carried out for all the cybrids to identify haplogroup and non-haplogroup defining SNPs. mtDNA can mediate cellular bioenergetics and expression levels of nuclear genes related to complement, inflammation and apoptosis. Sequencing data suggest that observed effects are not due to rare mtDNA variants but rather the combination of SNPs representing the J versus H haplogroups. These findings represent a paradigm shift in our concepts of mt-nuclear interactions.

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