1. ¹Department of Pathology, Emory University School of Medicine, Atlanta, GA, USA
2. ²Department of Medicine, National Jewish Medical Center, Denver, CO, USA
3. ³Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, NIH, Research Triangle, NC, USA
4. ⁴Department of Radiology, Emory University School of Medicine, Atlanta, GA, USA

Correspondence: Dr W Lewis, MD, Department of Pathology, Emory University School of Medicine, 7117 Woodruff Memorial Building, 101 Woodruff Circle, Atlanta, GA 30322, USA. E-mail: wlewis@emory.edu

Received 3 October 2006; Revised 14 November 2006; Accepted 15 November 2006; Published online 19 February 2006.

Abstract

POLG is the human gene that encodes the catalytic subunit of DNA polymerase (Pol ), 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 , mtDNA depletion, and mitochondrial oxidative stress to the mtDNA replication apparatus and to CM.