Cited by 435Mitochondrial Function and PathologyCardiac electrophysiology and arrhythmiasCardiomyopathy and Myosin Studies

The DOI matches its Crossref record; 31 of the 31 references it cites were found in a registry or an index.

Dilated cardiomyopathy and atrioventricular conduction blocks induced by heart-specific inactivation of mitochondrial DNA gene expression.

Abstract

Mutations of mitochondrial DNA (mtDNA) cause several well-recognized human genetic syndromes with deficient oxidative phosphorylation and may also have a role in ageing and acquired diseases of old age. We report here that hallmarks of mtDNA mutation disorders can be reproduced in the mouse using a conditional mutation strategy to manipulate the expression of the gene encoding mitochondrial transcription factor A (Tfam, previously named mtTFA), which regulates transcription and replication of mtDNA. Using a loxP-flanked Tfam allele (TfamloxP) in combination with a cre-recombinase transgene under control of the muscle creatinine kinase promoter, we have disrupted Tfam in heart and muscle. Mutant animals develop a mosaic cardiac-specific progressive respiratory chain deficiency, dilated cardiomyopathy, atrioventricular heart conduction blocks and die at 2-4 weeks of age. This animal model reproduces biochemical, morphological and physiological features of the dilated cardiomyopathy of Kearns-Sayre syndrome. Furthermore, our findings provide genetic evidence that the respiratory chain is critical for normal heart function.

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Crossref · 10.1038/5089

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Metadata

Authors
Wang, J., Wilhelmsson, H., Graff, C., Li, H., Oldfors, A., Rustin, P., Brüning, J. C., Kahn, C. R., Clayton, D. A., Barsh, G. S., Thorén, P., & Larsson, N.-G.
Affiliations
  • Karolinska University Hospital (SE)
  • Sahlgrenska University Hospital (SE)
  • Inserm (FR)
  • Joslin Diabetes Center (US)
  • Howard Hughes Medical Institute (US)
  • Karolinska Institutet (SE)
Corresponding author
Larsson, Nils-Göran
Venue
Nature Genetics
Published
1999-01
Volume
21
Issue
1
Pages
133-137
ISSN
  • 1061-4036 (ISSN-L)
  • 1546-1718
OpenAlex
W1548912336
Cited by
435
References
31
Citations by year
2026: 8 · 2025: 2 · 2024: 12 · 2023: 9 · 2022: 7 · 2021: 13 · 2020: 11 · 2019: 15 · 2018: 12 · 2017: 17 · 2016: 15 · 2015: 16 · 2014: 16 · 2013: 9 · 2012: 21
FWCI
9.30
Type
journal article
Language
en
Open access
closed
Locations
  • Nature Genetics (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (5r37gm033088-25)
  • National Institute of General Medical Sciences (R37-GM33088-28)
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
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiomyopathy and Myosin Studies
Keywords
dilated cardiomyopathy, atrioventricular block, mitochondrial DNA mutations, TFAM, Kearns-Sayre syndrome, conditional gene targeting, respiratory chain deficiency, oxidative phosphorylation, mouse model
MeSH terms
Animals, Cardiomyopathy, Dilated, Creatine Kinase, Electron Transport Complex IV, Disease Models, Animal, DNA-Binding Proteins, DNA, Mitochondrial, Female, Gene Expression Regulation, Heart, Heart Block, High Mobility Group Proteins, Humans, Male, Mice, Transgenic, Myocardium, Nuclear Proteins, Transcription Factors, Viral Proteins, Trans-Activators, NAD(P)H Dehydrogenase (Quinone), Muscle, Skeletal, Integrases, Mitochondrial Proteins, Xenopus Proteins, Mice

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