title: Transgenic mouse model with deficient mitochondrial polymerase exhibits reduced state IV respiration and enhanced cardiac fibrosis.
abstract: Mitochondria produce the energy required for proper cardiac contractile function, and cardiomyocytes that exhibit reduced mitochondrial electron transport will have reduced energy production and decreased contractility. Mitochondrial DNA (mtDNA) encodes the core subunits for the protein complexes of the electron transport chain (ETC). Reduced mtDNA abundance has been linked to reduced ETC and the development of heart failure in genetically engineered mice and in human diseases. Nucleoside reverse-transcriptase inhibitors for HIV/AIDS are used in antiretroviral regimens, which cause decreased mtDNA abundance by inhibiting the mitochondrial polymerase, pol-γ, as a limiting side effect. We explored consequences of AZT (1-[(2R,4S,5S)-4-azido-5-(hydroxymethyl)oxolan-2-yl]-5-methylpyrimidine-2,4-dione) exposure on mtDNA abundance in an established transgenic mouse model (TG) in which a cardiac-targeted mutant form of pol-γ displays a dilated cardiomyopathy (DCM) phenotype with increased left ventricle (LV)-mass and increased LV-end diastolic dimension. TG and wild-type littermate mice received 0.22 mg per day AZT or vehicle for 35 days, and were subsequently analyzed for physiological, histological, and molecular changes. After 35 days, Y955C TGs exhibited cardiac fibrosis independent of AZT. Reduced mtDNA abundance was observed in the Y955C mouse; AZT treatment had no effect on the depletion, suggesting that Y955C was sufficient to reduce mtDNA abundance maximally. Isolated mitochondria from AZT-treated Y955C hearts displayed reduced mitochondrial energetic function by oximetric measurement. AZT treatment of the Y955C mutation further reduced basal mitochondrial respiration and state IV(0) respiration. Together, these results demonstrate that defective pol-γ function promotes cardiomyopathy, cardiac fibrosis, mtDNA depletion, and reduced mitochondrial energy production.
authors.affiliation: Department of Pathology, Emory University, Atlanta, GA, USA.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Koczor
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Torres
authors.forename: Earl
authors.initials: E
authors.lastname: Fields
authors.forename: Qianhong
authors.initials: Q
authors.lastname: Qin
authors.forename: Jade
authors.initials: J
authors.lastname: Park
authors.forename: Tomika
authors.initials: T
authors.lastname: Ludaway
authors.forename: Rodney
authors.initials: R
authors.lastname: Russ
authors.forename: William
authors.initials: W
authors.lastname: Lewis
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D003433:Crosses, Genetic; D000074002:DNA Polymerase gamma; D017931:DNA Primers / Q000235:genetics; D004272:DNA, Mitochondrial / Q000235:genetics / Q000378:metabolism*; D004259:DNA-Directed DNA Polymerase / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D004452:Echocardiography; D004719:Endomyocardial Fibrosis / Q000150:complications*; D005838:Genotype; D006652:Histological Techniques; D006909:Hydroxyproline / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D028361:Mitochondrial Diseases / Q000150:complications* / Q000235:genetics / Q000503:physiopathology*; D020125:Mutation, Missense / Q000235:genetics; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology*; D010092:Oximetry; D012143:Respiratory Physiological Phenomena; D015215:Zidovudine / Q000494:pharmacology
chemical_list: D017931:DNA Primers; D004272:DNA, Mitochondrial; D015215:Zidovudine; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase; C498803:Polg protein, mouse; D006909:Hydroxyproline