Genetic modification of survival in tissue-specific knockout mice with mitochondrial cardiomyopathy
Open accessAbstract
We recently described a mouse model that reproduces important pathophysiological features of mitochondrial DNA (mtDNA) mutation diseases. The gene for mouse mitochondrial transcription factor A, Tfam (also called mtTFA), a nucleus-encoded key regulator of mtDNA expression, was targeted with loxP sites (Tfam(loxP)) and disrupted in vivo by transgenic expression of cre-recombinase from the muscle creatinine kinase (Ckmm) promoter. This promoter is active from embryonic day 13, and the knockouts had normal respiratory chain function in the heart at birth and developed mitochondrial cardiomyopathy postnatally. In this paper, we describe a heart-knockout strain obtained by mating Tfam(loxP) mice to animals expressing cre-recombinase from the alpha-myosin heavy chain (Myhca) promoter. This promoter is active from embryonic day 8, and the knockouts had onset of mitochondrial cardiomyopathy during embryogenesis. The age of onset of cardiac respiratory chain dysfunction can thus be controlled by temporal regulation of cre-recombinase expression. Further characterization demonstrated that approximately 75% of the knockouts died in the neonatal period, whereas, surprisingly, approximately 25% survived for several months before dying from dilated cardiomyopathy with atrioventricular heart conduction blocks. Modifying gene(s) affect the life span of the knockouts, because approximately 95% of the knockout offspring from an intercross of the longer-living knockouts survived the neonatal period. Thus, the tissue-specific knockouts we describe here not only reproduce important pathophysiological features of mitochondrial cardiomyopathy but also provide a powerful system by which to identify modifying genes of potential therapeutic value.
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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 [10]
Manipulating nuclear genes regulating mtDNA maintenance and replication (TFAM, POLG, PEO1) is a more successful approach to developing mouse models of mitochondrial disease.
“Alternative and more successful approaches to developing mouse models of mitochondrial disease involve manipulating the nuclear genes that regulate mtDNA maintenance and replication, such as TFAM [176][177][178][179][180][181][182], POLG ('Mutator' model) [183], and PEO1 (Twinkle; 'Deletor' model) [184].”
From Mitochondrial DNA mutations and human disease (2010) · cites this paper as [176]
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- Authors
- Li, H., Wang, J., Wilhelmsson, H., Hansson, A., Thorén, P., Duffy, J., Rustin, P., & Larsson, N.-G.
- Affiliations
- Karolinska University Hospital (SE)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2000-03-28
- Volume
- 97
- Issue
- 7
- Pages
- 3467-3472
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC16263
- OpenAlex
- W2108059964
- Cited by
- 185
- References
- 23
- Citations by year
- 2026: 5 · 2025: 1 · 2024: 8 · 2023: 6 · 2022: 6 · 2021: 6 · 2020: 4 · 2019: 6 · 2018: 6 · 2017: 5 · 2016: 7 · 2015: 10 · 2014: 7 · 2013: 3 · 2012: 6
- FWCI
- 4.10
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- 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
- mitochondrial cardiomyopathy, TFAM, tissue-specific knockout mice, Cre recombinase, neonatal mortality, dilated cardiomyopathy, atrioventricular block, modifying genes, survival
- MeSH terms
- Animals, Animals, Newborn, Cardiomyopathy, Dilated, Electron Transport, Embryo, Mammalian, Viral Proteins, Trans-Activators, Mitochondrial Myopathies, Mice, Knockout, Myosin Heavy Chains, Integrases, Xenopus Proteins, Mice
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