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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Loss of Tfam causes depletion of mtDNA, loss of mitochondrial transcripts, loss of mtDNA-encoded polypeptides, and severe respiratory chain deficiency.
“Loss of Tfam causes depletion of mtDNA, loss of mitochondrial transcripts, loss of mtDNA-encoded polypeptides, and severe respiratory chain deficiency (8)(9)(10)(11)(12).”
From Increased mitochondrial mass in mitochondrial myopathy mice (2002) · cites this paper as [9]
Control mice have normal Tfam expression, normal mtDNA copy number, and normal respiratory chain function in different tissues.
“Mice with the genotype Tfam loxP ͞Tfam loxP , hereafter referred to as ''control mice,'' were used as controls and have been shown previously to have normal Tfam expression, normal mtDNA copy number, and normal respiratory chain function in different tissues (9).”
From Increased mitochondrial mass in mitochondrial myopathy mice (2002) · cites this paper as [9]
Mouse models with decreased mtDNA expression have increased cell death with little or no increase of oxidative stress.
“We have studied a variety of mouse models with decreased mtDNA expression (10, 12–18) and such mice have increased cell death with little or no increase of oxidative stress (18, 30).”
From Progressive parkinsonism in mice with respiratory-chain-deficient dopamine neurons (2007) · cites this paper as [13]
Skeletal muscle-specific Tfam deficiency is accompanied by increased AMP kinase activation and increased glycolysis, indicating that compensatory mechanisms to maintain ATP levels are activated in response to impaired mitochondrial energetics.
“Skeletal muscle-specific Tfam deficiency is accompanied by increased AMP kinase activation and increased glycolysis, indicating that compensatory mechanisms to maintain ATP levels are activated in response to impaired mitochondrial energetics (282).”
From The role of mitochondria in the pathogenesis of type 2 diabetes (2010) · cites this paper as [282]
Skeletal and cardiac muscle-specific deletion of Tfam causes severe OXPHOS deficits, dilated cardiomyopathy, and death during early postnatal life.
“Similarly, skeletal and cardiac muscle-specific deletion of Tfam causes severe OXPHOS deficits, dilated cardiomyopathy, and death during early postnatal life (282).”
From The role of mitochondria in the pathogenesis of type 2 diabetes (2010) · cites this paper as [282]
In these mice, insulin sensitivity is normal and glucose tolerance is enhanced, consistent with a need for enhanced fuel utilization in response to inefficient mitochondrial ATP production.
“In these mice, insulin sensitivity is normal and glucose tolerance is enhanced, consistent with a need for enhanced fuel utilization in response to inefficient mitochondrial ATP production.”
From The role of mitochondria in the pathogenesis of type 2 diabetes (2010) · cites this paper as [282]
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- 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
- ORCID
- Venue
- Nature Genetics
- Published
- 1999-01
- Volume
- 21
- Issue
- 1
- Pages
- 133-137
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- DOI
- 10.1038/5089
- 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
- Licence
- www.springer.com/tdm (tdm)
- 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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