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

Age-relatedmaculardegeneration(AMD) is the leadingcauseof visionloss indevelopedcountries.While linkedto genetic polymorphisms in the complement pathway, there aremany individuals with high risk alleles that do not developAMD,suggestingthatother'modifiers'maybe involved.Mitochondrial (mt)haplogroups,definedby accumulationsof specificmtDNAsinglenucleotidepolymorphisms (SNPs)whichrepresentpopulationorigins,maybe one suchmodifier.Jhaplogrouphasbeenassociatedwithhighrisk forAMDwhile theHhaplogroupisprotective. It hasbeendifficult toassignbiologicalconsequencesforhaplogroupssowecreatedhumanARPE-19cybrids(cytoplasmic hybrids), which have identical nuclei but mitochondria of either J or H haplogroups, to investigate their effects upon bioenergetics andmolecular 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 bymtDNA. 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 andapoptosis.Sequencing data suggest thatobservedeffects arenotdue toraremtDNAvariantsbut rather the combinationofSNPsrepresentingtheJ versus H haplogroups. These findings represent a paradigm shift in our concepts of mt-nuclear interactions.