Premature ageing in mice expressing defective mitochondrial DNA polymerase

@article{Trifunovic2004PrematureAI,
  title={Premature ageing in mice expressing defective mitochondrial DNA polymerase},
  author={Aleksandra Trifunovic and Anna Wredenberg and Maria Falkenberg and Johannes N. Spelbrink and Anja T. Rovio and Carl E. G. Bruder and M Bohlooly-y and Sebastian Brusell Gidl{\"o}f and Anders Oldfors and Rolf Wibom and Jan T{\"o}rnell and Howard Trevor Jacobs and Nils-G{\"o}ran Larsson},
  journal={Nature},
  year={2004},
  volume={429},
  pages={417-423}
}
Point mutations and deletions of mitochondrial DNA (mtDNA) accumulate in a variety of tissues during ageing in humans, monkeys and rodents. These mutations are unevenly distributed and can accumulate clonally in certain cells, causing a mosaic pattern of respiratory chain deficiency in tissues such as heart, skeletal muscle and brain. In terms of the ageing process, their possible causative effects have been intensely debated because of their low abundance and purely correlative connection with… Expand
Germline mtDNA mutations aggravate ageing and can impair brain development
TLDR
It is reported that maternally transmitted mt DNA mutations can induce mild ageing phenotypes in mice with a wild-type nuclear genome and a pre-existing mutation load will not only allow somatic mutagenesis to create a critically high total mtDNA mutation load sooner but will also increase clonal expansion of mtDNA mutations to enhance the normally occurring mosaic respiratory chain deficiency in ageing tissues. Expand
The mtDNA mutator mouse: Dissecting mitochondrial involvement in aging
TLDR
Evidence is provided that the accumulation of point mutations in mt DNA leads to the synthesis of respiratory chain subunits with amino acid substitutions that impair complex stability in mtDNA mutator mice and it is demonstrated that the point mutations cause progressive respiratory chain deficiency, which, it is proposed, leads to premature aging. Expand
Different faces of mitochondrial DNA mutators.
TLDR
The role of different repair, replication and maintenance mechanisms that contribute to mtDNA integrity and mutagenesis will be discussed in details in this article. Expand
Mitochondrial DNA mutations may contribute to aging via cell death caused by peptides that induce cytochrome c release.
TLDR
Using computer simulation, it is shown that mitochondria with mtDNA mutations generate a peptide that causes the release of cytochrome c, providing a mechanism for the increased apoptosis observed in aging and that normal, age-related accumulation of mt DNA mutations causes significant levels of cell death. Expand
Mutations of mitochondrial DNA are not major contributors to aging of fruit flies
TLDR
It is reported here that lifespan and health in fruit flies are remarkably tolerant to mtDNA mutations, as exemplified by their lack of effect on physiology and lifespan. Expand
Mitochondrial DNA mutations in aging.
TLDR
The impact of somatic mtDNA mutations rapidly increases with age, so their importance is expected to grow as human life expectancy increases, and their significance is yet to be evaluated. Expand
Somatic mitochondrial DNA mutations do not increase neuronal vulnerability to MPTP in young POLG mutator mice.
TLDR
The hypothesis that somatic mtDNA mutations contribute to the age-related vulnerability of dopaminergic neurons to 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) increases with age is not supported. Expand
Molecular mechanisms of aging in MTDNA mutator mice
TLDR
The molecular mechanisms behind the mitochondrial dysfunction and premature aging phenotypes of the mtDNA mutator mice are examined and it is observed that UCP2 has a protective role in the mt DNA mutator hearts, perhaps through allowing better utilization of fatty acids. Expand
Germline and somatic mtDNA mutations in mouse aging
TLDR
It is suggested that, in contrast to humans, acquired somatic mtDNA mutations do not accompany the aging process in wt mice. Expand
Lifespan effects of mitochondrial mutations
TLDR
It is shown that similarly generated conplastic strains, which carry a nuclear Nnt mutation, do not show any alterations in these parameters, demonstrating the relevance of specific mitonuclear interactions in determining mammalian healthspan through increased production of ROS. Expand
...
1
2
3
4
5
...

References

SHOWING 1-10 OF 41 REFERENCES
Accumulation of point mutations in mitochondrial DNA of aging mice.
TLDR
The data suggest that at 22 months of age, which roughly corresponds to 3/4 of the mouse natural life span, most mtDNA molecules carry multiple point mutations, which exceeds existing estimates for mutation frequencies for nuclear genes by approximately 1000-fold. Expand
Ageing muscle: clonal expansions of mitochondrial DNA point mutations and deletions cause focal impairment of mitochondrial function
TLDR
The data show that mitochondrial DNA point mutations, as well as large-scale deletions, are associated with cytochrome c oxidase deficient muscle fibre segments in ageing, which causes significant impairment of mitochondrial function in individual cells in spite of low overall levels of mitochondrial DNA mutations in muscle. Expand
Mitochondrial DNA deletions in human brain: regional variability and increase with advanced age
TLDR
Changes in the accumulation of the common 4977 nucleotide pair (np) deletion in the cortex, putamen and cerebellum suggest that somatic mtDNA deletions might contribute to the neurological impairment often associated with ageing. Expand
A mitochondrial paradigm for degenerative diseases and ageing.
  • D. Wallace
  • Biology, Medicine
  • Novartis Foundation symposium
  • 2001
TLDR
The decline of mitochondrial energy production resulting in increased oxidative stress and apoptosis does play a significant role in degenerative diseases and ageing. Expand
Increased in vivo apoptosis in cells lacking mitochondrial DNA gene expression
  • Jianming Wang, José P. Silva, C. Gustafsson, P. Rustin, N. Larsson
  • Biology, Medicine
  • Proceedings of the National Academy of Sciences of the United States of America
  • 2001
TLDR
In vivo evidence is provided that respiratory chain deficiency predisposes cells to apoptosis, contrary to previous assumptions based on in vitro studies of cultured cells, which suggest that increased apoptosis is a pathogenic event in human mtDNA mutation disorders. Expand
In Vivo Functional Analysis of the Human Mitochondrial DNA Polymerase POLG Expressed in Cultured Human Cells*
TLDR
It is demonstrated that POLG exonuclease and polymerase functions are essential for faithful mtDNA maintenance in vivo, and the importance of key residues for these activities is indicated. Expand
Impaired insulin secretion and β-cell loss in tissue-specific knockout mice with mitochondrial diabetes
TLDR
This animal model reproduces the β-cell pathology of human mitochondrial diabetes and provides genetic evidence for a critical role of the respiratory chain in insulin secretion. Expand
Mitochondrial transcription factor A is necessary for mtDNA maintance and embryogenesis in mice
TLDR
The mouse gene for mitochondrial transcription factor A (Tfam), formerly known as m-mtTFA, is disrupted by gene targetting of loxP-sites followed by cre-mediated excision in vivo and is the first mammalian protein demonstrated to regulate mtDNA copy number in vivo. Expand
High levels of mitochondrial DNA deletions in skeletal muscle of old rhesus monkeys
TLDR
Analysis of defined numbers of cells from rhesus monkeys supports the hypothesis that mtDNA deletions can focally accumulate to high levels contributing to declines in mass and function of aging skeletal muscle. Expand
A switch in metabolism precedes increased mitochondrial biogenesis in respiratory chain-deficient mouse hearts.
  • A. Hansson, N. Hance, +5 authors N. Larsson
  • Biology, Medicine
  • Proceedings of the National Academy of Sciences of the United States of America
  • 2004
TLDR
It can be concluded that at least some of the secondary gene expression alterations in mitochondrial cardiomyopathy do not compensate but rather directly contribute to heart failure progression and likely aggravates the disease. Expand
...
1
2
3
4
5
...