Decreased mtDNA, oxidative stress, cardiomyopathy, and death from transgenic cardiac targeted human mutant polymerase gamma

• Type of Material: Article
• Authors: William Lewis, Emory University; Brian J. Day, National Jewish Medical Center; James J Kohler, Emory University; Seyed H. Hosseini, Emory University; Sherine S. L. Chan, National Institute of Environmental Health Sciences; Elgin Green, Emory University; Chad P. Haase, Emory University; Erin Keebaugh, Emory University; Robert Long Jr., Emory University; Tomika Ludaway, Emory University; Rodney Russ, Emory University; Jeffrey Steltzer, Emory University; Nina Tioleco, Emory University; Robert Santoianni, Emory University; William C. Copeland, National Institute of Environmental Health Sciences
• Language: English
• Date: 2007-04
• Publisher: Nature Publishing Group: Open Access Hybrid Model Option B
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2007 USCAP, Inc All rights reserved
• Final Published Version (URL): http://www.nature.com/labinvest/journal/v87/n4/full/3700523a.html
• Title of Journal or Parent Work: Laboratory Investigation
• ISSN: 0023-6837
• Volume: 87
• Issue: 4
• Start Page: 326
• End Page: 335
• Grant/Funding Information: This work was supported by DHHS, NIH, NHLBI R01 HL059798 and in part by HL072707 to WL and by NIH intramural research funds to WCC.
• Research Categories: Health Sciences, Pathology; Health Sciences, Radiology

Abstract

POLG is the human gene that encodes the catalytic subunit of DNA polymerase γ (Pol γ), the replicase for human 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 (EM) defined the phenotype. Cardiac targeted Y955C POLG yielded a molecular signature of CPEO in the heart with cardiomyopathy, 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 cardiomyopathy as it relates to the genetic defect in CPEO. The transgenic model pathophysiologically links human mutant Pol γ, mtDNA depletion and mitochondrial oxidative stress to the mtDNA replication apparatus and to cardiomyopathy.