Mitochondrial DNA variants mediate energy production and expression levels for CFH, C3 and EFEMP1 genes: implications for age-related macular degeneration.
BACKGROUND
Mitochondrial dysfunction is associated with the development and progression of age-related macular degeneration (AMD). Recent studies using populations from the United States and Australia have demonstrated that AMD is associated with mitochondrial (mt) DNA haplogroups (as defined by combinations of mtDNA polymorphisms) that represent Northern European Caucasians. The aim of this study was to use the cytoplasmic hybrid (cybrid) model to investigate the molecular and biological functional consequences that occur when comparing the mtDNA H haplogroup (protective for AMD) versus J haplogroup (high risk for AMD).


RESULTS
Cybrids were created by introducing mitochondria from individuals with either H or J haplogroups into a human retinal epithelial cell line (ARPE-19) that was devoid of mitochondrial DNA (Rho0). In cybrid lines, all of the cells carry the same nuclear genes but vary in mtDNA content. The J cybrids had significantly lower levels of ATP and reactive oxygen/nitrogen species production, but increased lactate levels and rates of growth. Q-PCR analyses showed J cybrids had decreased expressions for CFH, C3, and EFEMP1 genes, high risk genes for AMD, and higher expression for MYO7A, a gene associated with retinal degeneration in Usher type IB syndrome. The H and J cybrids also have comparatively altered expression of nuclear genes involved in pathways for cell signaling, inflammation, and metabolism.


CONCLUSIONS
Our findings demonstrate that mtDNA haplogroup variants mediate not only energy production and cell growth, but also cell signaling for major molecular pathways. These data support the hypothesis that mtDNA variants play important roles in numerous cellular functions and disease processes, including AMD.
Gavin Herbert Eye Institute, University of California Irvine, Irvine, California, United States of America. mkenney@uci.edu
M Cristina
MC
Kenney
Marilyn
M
Chwa
Shari R
SR
Atilano
Janelle M
JM
Pavlis
Payam
P
Falatoonzadeh
Claudio
C
Ramirez
Deepika
D
Malik
Tiffany
T
Hsu
Grace
G
Woo
Kyaw
K
Soe
Anthony B
AB
Nesburn
David S
DS
Boyer
Baruch D
BD
Kuppermann
S Michal
SM
Jazwinski
Michael V
MV
Miceli
Douglas C
DC
Wallace
Nitin
N
Udar
D000255:Adenosine Triphosphate / Q000096:biosynthesis; D002478:Cells, Cultured; D003176:Complement C3 / Q000235:genetics / Q000378:metabolism; D017242:Complement Factor H / Q000235:genetics / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000235:genetics* / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism*; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D006239:Haplotypes; D006801:Humans; D006822:Hybrid Cells / Q000378:metabolism* / Q000473:pathology; D019344:Lactic Acid / Q000378:metabolism; D008268:Macular Degeneration / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008928:Mitochondria / Q000235:genetics* / Q000378:metabolism; D008954:Models, Biological; D000081412:Myosin VIIa; D009218:Myosins / Q000235:genetics / Q000378:metabolism; D026361:Reactive Nitrogen Species / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D055213:Retinal Pigment Epithelium / Q000166:cytology / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*
C493495:CFH protein, human; D003176:Complement C3; D004272:DNA, Mitochondrial; C119630:EFEMP1 protein, human; D016326:Extracellular Matrix Proteins; C000631455:MYO7A protein, human; D000081412:Myosin VIIa; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D019344:Lactic Acid; D017242:Complement Factor H; D000255:Adenosine Triphosphate; D009218:Myosins