Cited by 121Mitochondrial Function and PathologyCardiac electrophysiology and arrhythmiasMetabolism and Genetic Disorders

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

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Lewis, William, Day, Brian J, Kohler, James J, Hosseini, Seyed H, Chan, Sherine S L, Green, Elgin C, Haase, Chad P, Keebaugh, Erin S +7 more·2007·Laboratory Investigation

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.

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  1. Horvath R, Hudson G, Ferrari G, et al. Phenotypic spectrum associated with mutations of the mitochondrial polymerase {gamma} gene. Brain 2006;129:1674-1684.

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Authors
Lewis, W., Day, B. J., Kohler, J. J., Hosseini, S. H., Chan, S. S. L., Green, E. C., Haase, C. P., Keebaugh, E. S., Long, R., Ludaway, T., Russ, R., Steltzer, J., Tioleco, N., Santoianni, R., & Copeland, W. C.
Affiliations
  • Emory University (US)
  • National Jewish Health (US)
  • National Institutes of Health (US)
Corresponding author
Lewis, William
Venue
Laboratory Investigation
Publisher
Elsevier BV
Published
2007-04
Volume
87
Issue
4
Pages
326-335
ISSN
0023-6837 (ISSN-L)
OpenAlex
W2008606982
Cited by
121
References
51
Citations by year
2026: 1 · 2025: 6 · 2024: 3 · 2023: 3 · 2022: 4 · 2021: 2 · 2020: 3 · 2019: 1 · 2018: 3 · 2017: 9 · 2016: 7 · 2015: 9 · 2014: 7 · 2013: 7 · 2012: 7
FWCI
4.91
Type
journal article
Language
en
Open access
Locations
  • Laboratory Investigation (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • U.S. Department of Health and Human Services
  • National Institutes of Health (NHLBI R01)
  • National Heart, Lung, and Blood Institute (R01HL072707, R01HL059798, HL072707)
  • National Institute of Environmental Health Sciences (Z01ES065080, Z01ES065078)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
Keywords
DNA polymerase gamma, chronic progressive external ophthalmoplegia, mitochondrial DNA depletion, mitochondrial oxidative stress, cardiomyopathy, transgenic mouse heart, 8-hydroxy-2'-deoxyguanosine, mitochondrial DNA replication, premature mortality, bradycardia, left ventricular hypertrophy
MeSH terms
DNA Polymerase gamma, 8-Hydroxy-2'-Deoxyguanosine, Animals, Deoxyguanosine, DNA-Directed DNA Polymerase, DNA, Mitochondrial, Heart Ventricles, Humans, Magnetic Resonance Imaging, Mice, Transgenic, Mitochondria, Heart, Mutation, Cardiomyopathies, Myocardium, Oxidative Stress, Mice

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