title: Molecular and bioenergetic differences between cells with African versus European inherited mitochondrial DNA haplogroups: implications for population susceptibility to diseases.
abstract: The geographic origins of populations can be identified by their maternally inherited mitochondrial DNA (mtDNA) haplogroups. This study compared human cybrids (cytoplasmic hybrids), which are cell lines with identical nuclei but mitochondria from different individuals with mtDNA from either the H haplogroup or L haplogroup backgrounds. The most common European haplogroup is H while individuals of maternal African origin are of the L haplogroup. Despite lower mtDNA copy numbers, L cybrids had higher expression levels for nine mtDNA-encoded respiratory complex genes, decreased ATP (adenosine triphosphate) turnover rates and lower levels of reactive oxygen species production, parameters which are consistent with more efficient oxidative phosphorylation. Surprisingly, GeneChip arrays showed that the L and H cybrids had major differences in expression of genes of the canonical complement system (5 genes), dermatan/chondroitin sulfate biosynthesis (5 genes) and CCR3 (chemokine, CC motif, receptor 3) signaling (9 genes). Quantitative nuclear gene expression studies confirmed that L cybrids had (a) lower expression levels of complement pathway and innate immunity genes and (b) increased levels of inflammation-related signaling genes, which are critical in human diseases. Our data support the hypothesis that mtDNA haplogroups representing populations from different geographic origins may play a role in differential susceptibilities to diseases.
authors.affiliation: Gavin Herbert Eye Institute, Univ. of California Irvine, Irvine, CA, USA; Department of Pathology and Laboratory Medicine, Univ. of California Irvine, Irvine, CA, USA. Electronic address: mkenney@uci.edu.
authors.forename: M Cristina
authors.initials: MC
authors.lastname: Kenney
authors.affiliation: Gavin Herbert Eye Institute, Univ. of California Irvine, Irvine, CA, USA.
authors.forename: Marilyn
authors.initials: M
authors.lastname: Chwa
authors.affiliation: Gavin Herbert Eye Institute, Univ. of California Irvine, Irvine, CA, USA.
authors.forename: Shari R
authors.initials: SR
authors.lastname: Atilano
authors.affiliation: Gavin Herbert Eye Institute, Univ. of California Irvine, Irvine, CA, USA.
authors.forename: Payam
authors.initials: P
authors.lastname: Falatoonzadeh
authors.affiliation: Gavin Herbert Eye Institute, Univ. of California Irvine, Irvine, CA, USA.
authors.forename: Claudio
authors.initials: C
authors.lastname: Ramirez
authors.affiliation: Gavin Herbert Eye Institute, Univ. of California Irvine, Irvine, CA, USA.
authors.forename: Deepika
authors.initials: D
authors.lastname: Malik
authors.affiliation: Gavin Herbert Eye Institute, Univ. of California Irvine, Irvine, CA, USA.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Tarek
authors.affiliation: Gavin Herbert Eye Institute, Univ. of California Irvine, Irvine, CA, USA.
authors.forename: Javier Cáceres
authors.initials: JC
authors.lastname: Del Carpio
authors.affiliation: Gavin Herbert Eye Institute, Univ. of California Irvine, Irvine, CA, USA; Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Anthony B
authors.initials: AB
authors.lastname: Nesburn
authors.affiliation: Retina-Vitreous Associates Medical Group, Beverly Hills, CA, USA.
authors.forename: David S
authors.initials: DS
authors.lastname: Boyer
authors.affiliation: Gavin Herbert Eye Institute, Univ. of California Irvine, Irvine, CA, USA.
authors.forename: Baruch D
authors.initials: BD
authors.lastname: Kuppermann
authors.affiliation: Functional Genomics Laboratory, Department of Psychiatry and Human Behavior, Univ. of California Irvine, Irvine, CA, USA.
authors.forename: Marquis P
authors.initials: MP
authors.lastname: Vawter
authors.affiliation: Tulane Center for Aging, Tulane University, New Orleans, LA, USA.
authors.forename: S Michal
authors.initials: SM
authors.lastname: Jazwinski
authors.affiliation: Tulane Center for Aging, Tulane University, New Orleans, LA, USA.
authors.forename: Michael V
authors.initials: MV
authors.lastname: Miceli
authors.affiliation: Children's Hospital of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Wallace
authors.affiliation: Gavin Herbert Eye Institute, Univ. of California Irvine, Irvine, CA, USA.
authors.forename: Nitin
authors.initials: N
authors.lastname: Udar
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000328:Adult; D044383:Black People / Q000235:genetics*; D002460:Cell Line; D049109:Cell Proliferation; D004272:DNA, Mitochondrial / Q000235:genetics*; D004734:Energy Metabolism / Q000235:genetics*; D018628:Gene Dosage; D020869:Gene Expression Profiling; D050259:Genes, Mitochondrial / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000208:ethnology / Q000235:genetics; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D006822:Hybrid Cells / Q000166:cytology / Q000378:metabolism; D007773:Lactates / Q000378:metabolism; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D044465:White People / Q000235:genetics*
chemical_list: D004272:DNA, Mitochondrial; D007773:Lactates; D017382:Reactive Oxygen Species; D000255:Adenosine Triphosphate
keywords: ABI; ARPE-19; ATP; Adenosine triphosphate; Applied Biosystems; C1s; C3; C4B; CFH; Carbonyl Cyanide 4-trifluoromethoxy-phenylhydrazone; Complement activation; Complement component 1, s subcomponent; Complement component 3; Complement component 4B; Complement factor H; Cybrid; DMEM; DNA; Deoxyribonucleic acid; Dulbecco's modified Eagle's medium; ECAR; EDTA; ETC; Electron transport chain; Ethylenediaminetetracetic acid; Extracellular acidification rate; FCCP; Haplogroup; Innate immunity; MT-CO1; MT-CO2; MT-CO3; MT-CYB; MT-ND1; MT-ND3; MT-ND5; Maximal oxygen uptake; MicroMolar; Mitochondria encoded NADH dehydrogenase 1; Mitochondria encoded NADH dehydrogenase 3; Mitochondria encoded NADH dehydrogenase 5; Mitochondria encoded cytochrome B; Mitochondria encoded cytochrome oxidase 1; Mitochondria encoded cytochrome oxidase 2; Mitochondria encoded cytochrome oxidase 3; Mitochondrion; OCR; OXPHOS; Oxidative phosphorylation; Oxygen consumption rate; Q-PCR; Quantitative polymerase chain reaction; Retina; Retinal pigmented epithelium cell line; SEM; SNPs; Single nucleotide polymorphisms; Standard error mean; UCLA; University of California, Los Angeles; VO2(max); μM