Decreased mtDNA, oxidative stress, cardiomyopathy, and death from transgenic cardiac targeted human mutant polymerase gamma.
POLG is the human gene that encodes the catalytic subunit of DNA polymerase gamma (Pol gamma), the replicase for human mitochondrial DNA (mtDNA). A POLG Y955C point mutation causes human chronic progressive external ophthalmoplegia (CPEO), a mitochondrial disease with eye muscle weakness and mtDNA defects. Y955C POLG was targeted transgenically (TG) to the murine heart. Survival was determined in four TG (+/-) lines and wild-type (WT) littermates (-/-). Left ventricle (LV) performance (echocardiography and MRI), heart rate (electrocardiography), mtDNA abundance (real time PCR), oxidation of mtDNA (8-OHdG), histopathology and electron microscopy defined the phenotype. Cardiac targeted Y955C POLG yielded a molecular signature of CPEO in the heart with cardiomyopathy (CM), mitochondrial oxidative stress, and premature death. Increased LV cavity size and LV mass, bradycardia, decreased mtDNA, increased 8-OHdG, and cardiac histopathological and mitochondrial EM defects supported and defined the phenotype. This study underscores the pathogenetic role of human mutant POLG and its gene product in mtDNA depletion, mitochondrial oxidative stress, and CM as it relates to the genetic defect in CPEO. The transgenic model pathophysiologically links human mutant Pol gamma, mtDNA depletion, and mitochondrial oxidative stress to the mtDNA replication apparatus and to CM.
Lewis
William
W
Department of Pathology, Emory University School of Medicine, Atlanta, GA 30322, USA. wlewis@emory.edu
Day
Brian J
BJ
Kohler
James J
JJ
Hosseini
Seyed H
SH
Chan
Sherine S L
SS
Green
Elgin C
EC
Haase
Chad P
CP
Keebaugh
Erin S
ES
Long
Robert
R
Ludaway
Tomika
T
Russ
Rodney
R
Steltzer
Jeffrey
J
Tioleco
Nina
N
Santoianni
Robert
R
Copeland
William C
WC
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D009202:Cardiomyopathies / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D000074002:DNA Polymerase gamma; D004272:DNA, Mitochondrial / Q000378:metabolism*; D004259:DNA-Directed DNA Polymerase / Q000235:genetics / Q000502:physiology*; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D006352:Heart Ventricles / Q000473:pathology; D006801:Humans; D008279:Magnetic Resonance Imaging; D051379:Mice; D008822:Mice, Transgenic; D008929:Mitochondria, Heart / Q000378:metabolism / Q000648:ultrastructure; D009154:Mutation; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress
D004272:DNA, Mitochondrial; D000080242:8-Hydroxy-2'-Deoxyguanosine; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase; C413027:POLG protein, human; D003849:Deoxyguanosine