Mice and mitochondria

It can be hard to work out whether particular events are a cause or a correlate of ageing — do mutations in mitochondrial DNA, for instance, speed up the process of growing old? Some clever studies suggest so.

Mitochondria are little pockets of energy within cells, shouldering the important task of converting food into usable energy forms. To meet demands, every cell contains thousands of them. Unlike most other cellular compartments, mitochondria have their own genomes, which encode a few mitochondrial proteins (most others being encoded by genes in the nucleus). In numerous non-reproductive tissues of many species, mitochondrial genes (like nuclear genes) accumulate mutations as the animals age1, and it has been speculated that these mutations might in fact cause ageing, by leading to energy-generation defects — increased numbers of harmful reactive oxygen species, cellular damage and so on. On the other hand, the association between mitochondrial mutations and ageing could merely be correlative — these mutations might simply be one of the manifestations of growing old. That possibility becomes less likely, however, with the publication of the paper on page 417 of this issue by Trifunovic and colleagues2.

Point mutations (single base-pair changes)3, deletions and rearrangements4 in mitochondrial DNA accumulate in several non-reproductive (somatic) tissues during ageing. To find out whether such alterations are a cause or a correlate of growing old, Trifunovic et al.2 genetically engineered mice to carry mutations in an enzyme called DNA polymerase-γ. Encoded by nuclear genes and transported to mitochondria, this protein is believed to be responsible for all aspects of mitochondrial DNA metabolism: it both copies and proofreads the DNA, eliminating errors it makes during replication, and it is also believed to participate in the resynthesis of DNA during DNA-repair processes. New mitochondria replace old mitochondria in all cell types throughout life, and new mitochondria must also be made when cells divide. These events require the replication of mitochondrial DNA.

Trifunovic and colleagues wanted to render the mitochondrial DNA polymerase error-prone by eliminating its proofreading activity while maintaining its catalytic potency — the rationale being that any errors in mitochondrial DNA replication would go unnoticed by the cell, and so mutations would accumulate. As the mice would have this error-prone polymerase from youth, it would be possible to see whether or not the mutations it produces accelerate ageing. To eliminate the proofreading activity, the authors substituted an alanine amino acid for a crucial aspartate in the relevant region of the enzyme molecule.

They found that the somatic tissues of mice bearing two mutant copies of the DNA polymerase-γ gene indeed showed extensive mitochondrial DNA mutations, largely comprising deletions and point mutations. The percentage of mitochondria bearing deletions was similar in different tissues, and did not vary with age, suggesting that the deletions had occurred early in development. The deletions seemed to have converted the normally circular mitochondrial DNA into linear molecules, which might not be functional inside cells.

Point mutations were also common; one mitochondrial enzyme, for instance — cytochrome b — had a three- to fivefold increase in single-base substitutions, randomly dispersed throughout the gene. The mutant animals also showed a decrease in the activity of enzymes involved in the respiratory chain (a crucial series of events in respiration) and the production of ATP (the main cellular energy store), which could be a result of both the deletions and the point mutations. The mutant mitochondrial DNA molecules were present together with normal copies, but sometimes a particular mutation would come to dominate — a situation comparable to that seen in ageing humans5.

Strikingly, the mutant mice showed symptoms consistent with accelerated ageing, such as premature weight loss, hair loss, reductions in fertility, curvature of the spine and a shortened lifespan. The symptoms began to emerge at about 25 weeks of age — young adulthood, in mouse terms. These findings strongly support the idea that mutations in mitochondrial DNA can cause at least some features resembling ageing. This delayed, post-maturational expression of overt signs of ageing is an important feature of any useful model system for studying the mechanisms by which organisms grow old.

Trifunovic and colleagues' findings are also consistent with the oxidative-damage theory of ageing — the idea that ageing is caused by an increase in the steady-state levels of reactive oxygen species and by proton ‘leaks’. Such events can result from mutations in respiratory-chain proteins.

Interestingly, there is a human disease that might be considered as a parallel to these mutant mice. Like mouse DNA polymerase-γ, the human enzyme contains DNA-synthesizing and proofreading domains6. Mutations in the proofreading domain are among the genetic alterations responsible for a rare inherited human disease, progressive external ophthalmoplegia7, which is characterized by paralysis of the eye muscles and various effects on other organs, and by the accumulation of mitochondrial mutations in non-reproductive tissues8. Like other mitochondrially linked, inherited disorders, the disease typically exhibits a delayed onset and a progressive course — features shared with ageing.

As with the mutant mice, however, many characteristics of interest to gerontologists have not been investigated in the rare affected people. More information is needed, in both mice and humans, about the ages of onset and rates of progression of cataracts, visual degeneration and hearing loss, and changes in immunity, hormones, cognitive functions and other traits.

Nonetheless, Trifunovic and colleagues' elegant study2 establishes that several manifestations of ageing in mice can result from mutations in DNA polymerase-γ that induce error-prone mitochondrial DNA synthesis. These results do not, however, imply that this is the only pathway that generates abnormalities resembling ageing. There are several other DNA-replicating and proofreading polymerases (α, β and δ) that function in the nucleus, as well as at least eight newly discovered, naturally error-prone polymerases that are believed to function in bypassing nuclear DNA lesions or in specialized processes that affect DNA9. These nuclear enzymes might, when mutated, each lead to further genetic alterations in certain somatic tissues and so accelerate ageing. If experiments show this to be the case, these polymerases will join the growing list of proteins that, when mutated in mice, produce groups of features that hint at an acceleration of particular aspects of ageing (‘segmental ageing’; Fig. 1); many of the mutations could act by enhancing genomic instability.

Figure 1: Many mutational pathways can accelerate ‘segmental ageing’ (or, to use more conservative nomenclature, segmental ageing-like syndromes) in mice.

Published literature2,11,12,13,14,15,16 suggests that there may be at least six pathways that generate partially overlapping subsets of features consistent with accelerated ageing. Several of these pathways are likely to interact17, making such classifications problematic. Trifunovic and colleagues' findings2, however, provide strong direct support for the mitochondrial pathway.

Of higher priority, however, would be experiments aimed at finding ways of maintaining the structure and function of tissues and organs for longer periods — leading to lengthened, not abbreviated, lifespans. We therefore look forward to the availability of mice that have been modified to bear a mitochondrial DNA polymerase that is more accurate than the normal enzyme.


  1. 1

    Vijg, J. Mutat. Res. 447, 117–135 (2000).

    CAS  Article  Google Scholar 

  2. 2

    Trifunovic, A. et al. Nature 429, 417–423 (2004).

    ADS  CAS  Article  Google Scholar 

  3. 3

    Wang, Y. et al. Proc. Natl Acad. Sci. USA 98, 4022–4027 (2001).

    ADS  CAS  Article  Google Scholar 

  4. 4

    Melov, S., Hinerfeld, D., Esposito, L. & Wallace, D. C. Nucleic Acids Res. 25, 974–982 (1997).

    CAS  Article  Google Scholar 

  5. 5

    Nekhaeva, E. et al. Proc. Natl Acad. Sci. USA 99, 5521–5526 (2002).

    ADS  CAS  Article  Google Scholar 

  6. 6

    Lim, S. E., Longley, M. J. & Copeland, W. C. J. Biol. Chem. 274, 38197–38203 (1999).

    CAS  Article  Google Scholar 

  7. 7

    Agostino, A. et al. Neurology 60, 1354–1356 (2003).

    CAS  Article  Google Scholar 

  8. 8

    Del Bo, R. et al. Neurology 61, 903–908 (2003).

    CAS  Article  Google Scholar 

  9. 9

    Shcherbakova, P. V., Bebenek, K. & Kunkel, T. A. Science Sci. Aging Knowledge Environ. doi:10.1126/sageke.2003.8.re3 (2003).

  10. 10

    Martin, G. M. Birth Defects Orig. Artic. Ser. 14, 5–39 (1978).

    CAS  PubMed  Google Scholar 

  11. 11

    Mounkes, L. C., Kozlov, S., Hernandez, L., Sullivan, T. & Stewart, C. L. Nature 423, 298–301 (2003).

    ADS  CAS  Article  Google Scholar 

  12. 12

    Vogel, H., Lim, D. S., Karsenty, G., Finegold, M. & Hasty, P. Proc. Natl Acad. Sci. USA 96, 10770–10775 (1999).

    ADS  CAS  Article  Google Scholar 

  13. 13

    De Boer, J. et al. Science 296, 1276–1279 (2002).

    ADS  CAS  Article  Google Scholar 

  14. 14

    Rudolph, K. L. et al. Cell 96, 701–712 (1999).

    CAS  Article  Google Scholar 

  15. 15

    Tyner, S. D. et al. Nature 415, 45–53 (2002).

    ADS  CAS  Article  Google Scholar 

  16. 16

    Nabeshima, Y. Ageing Res. Rev. 1, 627–638 (2002).

    CAS  Article  Google Scholar 

  17. 17

    Orsini, F. J. Biol. Chem. doi:10.1074/jbc.M401844200 (2004).

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Martin, G., Loeb, L. Mice and mitochondria. Nature 429, 357–359 (2004).

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