Mitochondrial dysfunction as a cause of ageing

  title={Mitochondrial dysfunction as a cause of ageing},
  author={Aleksandra Trifunovic and Nils-G{\"o}ran Larsson},
  journal={Journal of Internal Medicine},
Mitochondrial dysfunction is heavily implicated in the ageing process. Increasing age in mammals correlates with accumulation of somatic mitochondrial DNA (mtDNA) mutations and decline in respiratory chain function. The age‐associated respiratory chain deficiency is typically unevenly distributed and affects only a subset of cells in various human tissues, such as heart, skeletal muscle, colonic crypts and neurons. Studies of mtDNA mutator mice has shown that increased levels of somatic mtDNA… 

Somatic mitochondrial DNA mutations in mammalian aging.

  • N. Larsson
  • Biology
    Annual review of biochemistry
  • 2010
Emerging data instead suggest that the inherent error rate of mitochondrial DNA (mtDNA) polymerase gamma (Pol gamma) may be responsible for the majority of somatic mtDNA mutations.

Molecular mechanisms of aging in MTDNA mutator mice

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.

The role of mitochondrial DNA mutations and free radicals in disease and ageing

Evidence from an increasing number of experimental studies has suggested that mtDNA mutations may be generated by replication errors rather than by accumulated oxidative damage, leading to the emergence of new theories of how age‐associated mitochondrial dysfunction may lead to ageing.


The molecular mechanisms behind the mitochondrial dysfunction and premature aging phenotypes of the mtDNA mutator mice are examined and it is indicated that UCP2 has a protective role in the mt DNA mutator hearts, perhaps through allowing better utilization of fatty acids.

The mtDNA mutator mouse: Dissecting mitochondrial involvement in aging

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.

Detecting respiratory chain deficiency in osteoblasts of older patients

Significant increases in complex I deficiency with age in human osteoblasts are demonstrated, which suggests that respiratory chain deficiency, as a consequence of the accumulation of age related mitochondrial DNA mutations, may have a significant role to play in the pathogenesis of human age related osteoporosis.

Age-associated mosaic respiratory chain deficiency causes trans-neuronal degeneration

The minimal threshold level of respiratory chain-deficient neurons needed to cause symptoms is defined and it is demonstrated that neurons with normal respiratory chain function are able to ameliorate disease progression and induce death of normal neurons by a trans-neuronal degeneration mechanism.

Defects in multiple complexes of the respiratory chain are present in ageing human colonic crypts

Combination of mitochondrial tRNA and OXPHOS mutation reduces lifespan and physical condition in aged mice

The combination of both point mutations in the OXPHOS complex IV gene and adenine insertions in the mitochondrially encoded tRNA arginine (tRNA-Arg) gene (mt-Tr) leads to an age-dependent phenotype with elevated mitochondrial superoxide production in the neocortex, suggesting a synergistic effect of these mutations.



Mitochondria and Ageing

The decline of respiratory chain function with ageing represents an important factor for the decline of functional organ reserve capacity in senescence.

Somatic mtDNA mutations cause aging phenotypes without affecting reactive oxygen species production.

The premature aging phenotypes in mt DNA mutator mice are thus not generated by a vicious cycle of massively increased oxidative stress accompanied by exponential accumulation of mtDNA mutations, and it is proposed that respiratory chain dysfunction per se is the primary inducer of premature aging in mtDNA mutATOR mice.

Premature ageing in mice expressing defective mitochondrial DNA polymerase

The results provide a causative link between mtDNA mutations and ageing phenotypes in mammals by creating homozygous knock-in mice that express a proof-reading-deficient version of PolgA, the nucleus-encoded catalytic subunit of mtDNA polymerase.

Mitochondrial DNA Mutations, Oxidative Stress, and Apoptosis in Mammalian Aging

It is shown that mice expressing a proofreading-deficient version of the mitochondrial DNA polymerase g (POLG) accumulate mt DNA mutations and display features of accelerated aging, suggesting that accumulation of mtDNA mutations that promote apoptosis may be a central mechanism driving mammalian aging.

Deletions of muscle mitochondrial DNA in patients with mitochondrial myopathies

Observations demonstrate that mtDNA heteroplasmy can occur in man and that human disease may be associated with defects of the mitochondrial genome.

Increased in vivo apoptosis in cells lacking mitochondrial DNA gene expression

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.

Mitochondrial DNA mutations in human colonic crypt stem cells.

The accumulation of mtDNA mutations in human colonic crypt stem cells that result in a significant biochemical defect in their progeny are described, which has important consequences not only for understanding of the finding of mt DNA mutations in aging tissues and tumors, but also for determining the frequency ofmtDNA mutations within a cell.

Molecular genetic aspects of human mitochondrial disorders.

This review focuses on mutations of mitochondrial DNA (mtDNA) which are an important cause of mitochondrial disorders in humans and are also associated with common neurodegenerative disorders and