Online citations, reference lists, and bibliographies.
Please confirm you are human
(Sign Up for free to never see this)
← Back to Search

Dilated Cardiomyopathy And Atrioventricular Conduction Blocks Induced By Heart-specific Inactivation Of Mitochondrial DNA Gene Expression

J. Wang, H. Wilhelmsson, C. Graff, H. Li, A. Oldfors, P. Rustin, J. Brüning, C. Kahn, D. Clayton, G. Barsh, P. Thorén, N. Larsson
Published 1999 · Biology, Medicine

Save to my Library
Download PDF
Analyze on Scholarcy
Share
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 (Refs 6,7). Using a loxP-flanked Tfam allele (TfamloxP; ref. 8) in combination with a cre-recombinase transgene under control of the muscle creatinine kinase promoter9,10, 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.
This paper references
10.1126/SCIENCE.2035027
Similarity of human mitochondrial transcription factor 1 to high mobility group proteins.
M. Parisi (1991)
clinical and molecular analysis
E. A. Schon (1995)
10.1007/BF00763100
Mitochondrial encephalomyopathies: Clinical and molecular analysis
E. Schon (1994)
10.1161/01.RES.25.4.473
Biochemical correlates of cardiac hypertrophy. IV. Observations on the cellular organization of growth during myocardial hypertrophy in the rat.
D. Grove (1969)
Development and Proliferative Capacity of Cardiac Muscle Cells
R. Zak (1974)
10.1146/ANNUREV.CB.07.110191.002321
Replication and transcription of vertebrate mitochondrial DNA.
D. Clayton (1991)
10.1161/01.RES.77.3.632
In vivo echocardiographic detection of enhanced left ventricular function in gene-targeted mice with phospholamban deficiency.
B. Hoit (1995)
Regression analysis of relative survival
T. Hakulinen (1987)
Developmental regulation of creatine kinase gene expression by myogenic factors in embryonic mouse and chick skeletal muscle.
G. Lyons (1991)
10.1073/PNAS.88.23.10614
Introduction of disease-related mitochondrial DNA deletions into HeLa cells lacking mitochondrial DNA results in mitochondrial dysfunction.
J. Hayashi (1991)
10.1016/0167-4781(90)90039-5
Tissue-specific distribution and developmental regulation of M and B creatine kinase mRNAs.
R. Trask (1990)
heredity, heteroplasmy and disease
R. N. Lightowlers (1997)
10.1203/00006450-199008000-00011
Progressive Increase of the Mutated Mitochondrial DNA Fraction in Kearns-Sayre Syndrome
N. Larsson (1990)
10.1016/0169-2607(93)90065-S
A PC-based on-line system for physiological in vivo and in vitro experiments.
J. Axenborg (1993)
Segregation and manifestations of the mtDNA tRNA(Lys) A-->G(8344) mutation of myoclonus epilepsy and ragged-red fibers (MERRF) syndrome.
N. Larsson (1992)
10.1038/NG1295-376
Dilated cardiomyopathy and neonatal lethality in mutant mice lacking manganese superoxide dismutase
Y. Li (1995)
10.1016/0022-510X(92)90025-G
Mitochondrial DNA deletions and cytochrome c oxidase deficiency in muscle fibres
A. Oldfors (1992)
10.1016/0002-8703(80)90224-0
Constituents of the human ventricular myocardium: connective tissue hyperplasia accompanying muscular hypertrophy.
G. Moore (1980)
10.1038/NG0398-231
Mitochondrial transcription factor A is necessary for mtDNA maintance and embryogenesis in mice
N. Larsson (1998)
10.1016/0046-8177(92)90065-B
In situ hybridization of mitochondrial DNA in the heart of a patient with Kearns-Sayre syndrome and dilatative cardiomyopathy.
J. Mueller-Hoecker (1992)
10.1016/0009-8981(94)90055-8
Biochemical and molecular investigations in respiratory chain deficiencies.
P. Rustin (1994)
A new mtDNA mutation showing accumulation with time and restriction to skeletal muscle.
K. Weber (1997)
10.1038/ng0797-226
A mouse model for mitochondrial myopathy and cardiomyopathy resulting from a deficiency in the heart/muscle isoform of the adenine nucleotide translocator
B. Graham (1997)
10.1016/0092-8674(90)90238-A
Deletion mutants are functionally dominant over wild-type mitochondrial genomes in skeletal muscle fiber segments in mitochondrial disease
E. Shoubridge (1990)
10.1016/S0168-9525(97)01266-3
Mammalian mitochondrial genetics: heredity, heteroplasmy and disease.
R. Lightowlers (1997)
10.2307/2347789
Regression Analysis of Relative Survival Rates
T. Hakulinen (1987)
10.1046/J.1365-201X.1997.00134.X
The effects of triiodothyronine (T3) on heart rate, temperature and ECG measured with telemetry in freely moving mice.
C. Johansson (1997)
10.1161/01.RES.23.3.451
Biochemical Correlates of Cardiac Hypertrophy: I. Experimental Model; Changes in Heart Weight, RNA Content, and Nuclear RNA Polymerase Activity
K. Nair (1968)
10.1038/ng0892-359
Molecular analysis of the muscle pathology associated with mitochondrial DNA deletions
Carlos T. Moraes (1992)
10.1146/ANNUREV.GE.29.120195.001055
Molecular genetic aspects of human mitochondrial disorders.
N. Larsson (1995)
10.1126/SCIENCE.1533953
Mitochondrial genetics: a paradigm for aging and degenerative diseases?
D. Wallace (1992)
10.1002/ANA.410010104
Lumping or splitting? “ophthalmoplegia‐plus” or kearns‐sayre syndrome?
R. A. Berenberg (1977)
10.1006/ABBI.1996.0369
Tissue-specific stability of nuclear- and mitochondrially encoded mRNAs.
Michael K. Connor (1996)



This paper is referenced by
Elucidation of the role of the MICOS complex in signal transduction from mitocondrial DNA nucleoids
Michael Hellman (2015)
10.1093/gerona/glq109
Molecular adaptations to aerobic exercise training in skeletal muscle of older women.
A. Konopka (2010)
10.3389/fnmol.2019.00040
Mitochondrial Dysfunction in Astrocytes Impairs the Generation of Reactive Astrocytes and Enhances Neuronal Cell Death in the Cortex Upon Photothrombotic Lesion
C. Fiebig (2019)
Impaired mtDNA replication precedes mtDNA depletion in pressure overload-induced cardiac hypertrophy and heart failure
J. Shi (2009)
10.1128/MCB.01807-08
PLRG1 Is an Essential Regulator of Cell Proliferation and Apoptosis during Vertebrate Development and Tissue Homeostasis
A. Kleinridders (2009)
10.1007/s00335-001-2052-8
Downregulation of Tfam and mtDNA copy number during mammalian spermatogenesis
Anja Rantanen (2001)
10.1210/er.2009-0027
The role of mitochondria in the pathogenesis of type 2 diabetes.
Mary-Elizabeth Patti (2010)
10.1080/15216540600686888
Mitochondrial DNA mutations in human disease
L. Greaves (2006)
10.1002/hep.24547
Conditional disruption of mouse HFE2 gene: Maintenance of systemic iron homeostasis requires hepatic but not skeletal muscle hemojuvelin
Konstantinos Gkouvatsos (2011)
10.1083/jcb.200403004
Rb is required for progression through myogenic differentiation but not maintenance of terminal differentiation
M. Huh (2004)
10.1101/GAD.1458906
Targeted ablation of ILK from the murine heart results in dilated cardiomyopathy and spontaneous heart failure.
D. E. White (2006)
10.1093/HUMREP/15.SUPPL_2.18
Genetic control of oxidative phosphorylation and experimental models of defects.
I. Trounce (2000)
10.2183/pjab.84.155
Reverse genetic studies of mitochondrial DNA-based diseases using a mouse model
Kazuto Nakada (2008)
10.1155/2008/253817
The PPARα-PGC-1α Axis Controls Cardiac Energy Metabolism in Healthy and Diseased Myocardium
J. Duncan (2008)
10.1007/978-1-60327-514-9_15
Reactive Oxygen Species in Mitochondrial Encephalomyopathy: Mechanisms and Effects
S. Park (2011)
10.1016/J.YJMCC.2004.10.010
Mouse models of mitochondrial dysfunction and heart failure.
Laurie K. Russell (2005)
10.1096/fj.03-0520fje
Activity of complex III of the mitochondrial electron transport chain is essential for early heart muscle cell differentiation
D. Spitkovsky (2004)
10.1038/s41586-020-03048-z
Small-molecule inhibitors of human mitochondrial DNA transcription.
N. A. Bonekamp (2020)
10.1093/HUMREP/15.SUPPL_2.86
Regulation of mitochondrial DNA copy number during spermatogenesis.
Anja Rantanen (2000)
10.1093/hmg/dds352
Mitofusin 2 is necessary for striatal axonal projections of midbrain dopamine neurons.
Seungmin Lee (2012)
10.1007/978-1-60761-147-9_7
Signaling Cascades in Heart Failure: From Cardiomyocytes Growth and Survival to Mitochondrial Signaling Pathways
José Marín-García (2010)
10.1016/j.bbrc.2015.09.072
Mouse somatic mutation orthologous to MELAS A3302G mutation in the mitochondrial tRNA(Leu(UUR)) gene confers respiration defects.
A. Shimizu (2015)
The pathophysiology of respiratory chain dysfunction
J. P. Silva (2005)
10.33549/physiolres.932179
Modelling mitochondrial dysfunction in mice.
S. Dogan (2011)
10.1152/ajpcell.00076.2008
Alterations in mitochondrial function and cytosolic calcium induced by hyperglycemia are restored by mitochondrial transcription factor A in cardiomyocytes.
J. Suarez (2008)
10.1007/978-0-387-74072-0_7
Cardiomyopathy and Heart Failure in Aging
J. Marín-García (2008)
10.1152/AJPENDO.00255.2001
Reduced activity of mtTFA decreases the transcription in mitochondria isolated from diabetic rat heart.
A. Kanazawa (2002)
10.1038/82826
Generation of mice with mitochondrial dysfunction by introducing mouse mtDNA carrying a deletion into zygotes
K. Inoue (2000)
10.1067/MHJ.2001.112088
The emerging concept of mitochondrial cardiomyopathies.
F. Santorelli (2001)
10.1161/CIRCULATIONAHA.117.031417
FUNDC1: A Novel Protein in Cardiac Health
J. Muñoz (2017)
10.1201/9780203912874.pt2
Mitochondrial Dysfunction in Genetic Diseases
I. Scheffler (2003)
10.1128/EC.00092-14
The Strictly Aerobic Yeast Yarrowia lipolytica Tolerates Loss of a Mitochondrial DNA-Packaging Protein
Jana Bakkaiova (2014)
See more
Semantic Scholar Logo Some data provided by SemanticScholar