Decreased mtDNA, oxidative stress, cardiomyopathy, and death from transgenic cardiac targeted human mutant polymerase γ View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2007-04

AUTHORS

William Lewis, Brian J Day, James J Kohler, Seyed H Hosseini, Sherine S L Chan, Elgin C Green, Chad P Haase, Erin S Keebaugh, Robert Long, Tomika Ludaway, Rodney Russ, Jeffrey Steltzer, Nina Tioleco, Robert Santoianni, William C Copeland

ABSTRACT

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. More... »

PAGES

3700523

References to SciGraph publications

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/labinvest.3700523

DOI

http://dx.doi.org/10.1038/labinvest.3700523

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1022971840

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/17310215


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