Ageing: mice and mitochondria.
- SourceAvailable from: Marek Foksinski[show abstract] [hide abstract]
ABSTRACT: DNA damage and DNA repair may mediate several cellular processes, like replication and transcription, mutagenesis and apoptosis and thus may be important factors in the development and pathology of an organism, including cancer. DNA is constantly damaged by reactive oxygen species (ROS) and reactive nitrogen species (RNS) directly and also by products of lipid peroxidation (LPO), which form exocyclic adducts to DNA bases. A wide variety of oxidatively-generated DNA lesions are present in living cells. 8-oxoguanine (8-oxoGua) is one of the best known DNA lesions due to its mutagenic properties. Among LPO-derived DNA base modifications the most intensively studied are ethenoadenine and ethenocytosine, highly miscoding DNA lesions considered as markers of oxidative stress and promutagenic DNA damage. Although at present it is impossible to directly answer the question concerning involvement of oxidatively damaged DNA in cancer etiology, it is likely that oxidatively modified DNA bases may serve as a source of mutations that initiate carcinogenesis and are involved in aging (i.e. they may be causal factors responsible for these processes). To counteract the deleterious effect of oxidatively damaged DNA, all organisms have developed several DNA repair mechanisms. The efficiency of oxidatively damaged DNA repair was frequently found to be decreased in cancer patients. The present work reviews the basis for the biological significance of DNA damage, particularly effects of 8-oxoGua and ethenoadduct occurrence in DNA in the aspect of cancer development, drawing attention to the multiplicity of proteins with repair activities.American Journal of Translational Research 01/2010; 2(3):254-84.
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ABSTRACT: The mitochondrial theory of aging predicts that functional alterations in mitochondria leading to reactive oxygen species (ROS) production contribute to the aging process in most if not all species. Using cellular senescence as a model for human aging, we have recently reported partial uncoupling of the respiratory chain in senescent human fibroblasts. In the present communication, we address a potential cause-effect relationship between impaired mitochondrial coupling and premature senescence. Chronic exposure of human fibroblasts to the chemical uncoupler carbonylcyanide p-trifluoromethoxyphenylhydrazone (FCCP) led to a temporary, reversible uncoupling of oxidative phosphorylation. FCCP inhibited cell proliferation in a dose-dependent manner, and a significant proportion of the cells entered premature senescence within 12 days. Unexpectedly, chronic exposure of cells to FCCP led to a significant increase in ROS production, and the inhibitory effect of FCCP on cell proliferation was eliminated by the antioxidant N-acetyl-cysteine. However, antioxidant treatment did not prevent premature senescence, suggesting that a reduction in the level of oxidative phosphorylation contributes to phenotypical changes characteristic of senescent human fibroblasts. To assess whether this mechanism might be conserved in evolution, the influence of mitochondrial uncoupling on replicative life span of yeast cells was also addressed. Similar to our findings in human fibroblasts, partial uncoupling of oxidative phsophorylation in yeast cells led to a substantial decrease in the mother-cell-specific life span and a concomitant incrase in ROS, indicating that life span shortening by mild mitochondrial uncoupling may represent a "public" mechanism of aging.Free Radical Biology and Medicine 10/2007; 43(6):947-58. · 5.27 Impact Factor
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ABSTRACT: The notion of a mobile pool of coenzyme Q (CoQ) in the lipid bilayer has changed with the discovery of respiratory supramolecular units, in particular the supercomplex comprising complexes I and III; in this model, the electron transfer is thought to be mediated by tunneling or microdiffusion, with a clear kinetic advantage on the transfer based on random collisions. The CoQ pool, however, has a fundamental function in establishing a dissociation equilibrium with bound quinone, besides being required for electron transfer from other dehydrogenases to complex III. The mechanism of CoQ reduction by complex I is analyzed regarding recent developments on the crystallographic structure of the enzyme, also in relation to the capacity of complex I to generate superoxide. Although the mechanism of the Q-cycle is well established for complex III, involvement of CoQ in proton translocation by complex I is still debated. Some additional roles of CoQ are also examined, such as the antioxidant effect of its reduced form and the capacity to bind the permeability transition pore and the mitochondrial uncoupling proteins. Finally, a working hypothesis is advanced on the establishment of a vicious circle of oxidative stress and supercomplex disorganization in pathological states, as in neurodegeneration and cancer.BioFactors 09/2011; 37(5):330-54. · 3.09 Impact Factor
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NATURE|VOL 429|27 MAY 2004|www.nature.com/nature
Mice and mitochondria
George M. Martin and Lawrence A. Loeb
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.
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 ofmany 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 age-
ing could merely be correlative — these
mutations might simply be one of the mani-
festations of growing old. That possibility
becomes less likely,however,with the publi-
cation 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.2genetically engineered mice
to carry mutations in an enzyme called DNA
polymerase-?.Encoded by nuclear genes and
transported to mitochondria, this protein is
itochondria are little pockets of
energy within cells,shouldering the
important task of converting food
Lamin A/C (ref. 11)
Ku86, XPD (refs 12, 13)
DNA polymerase-γ (ref. 2)
p53 (ref. 15)
Klotho (ref. 16)
Defective inner nuclear membrane
Defective metabolism of nuclear DNA
Defective metabolism of mitochondrial DNA
Defective regulation of chromosome caps
Altered regulation of cell-division cycle and cell death
Impaired calcium and vitamin D metabolism?
Figure 1 Many mutational pathways can accelerate ‘segmental ageing’(or,to use more conservative
nomenclature,segmental ageing-like syndromes10) in mice.Published literature2,11–16suggests 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
Booker et al.1explain the deep melting by
invoking the ideas ofBercovici and Karato11.
This new hypothesis suggests that a layer of
melt exists just above the 410-km boundary
as slowly upwelling mantle undergoes a
change from water-rich wadsleyite to
olivine,liberating water and inducing melt-
ing. In Booker and colleagues’ models, the
melt column seems to originate as much
from the 410-km boundary as it does from
the subducting slab,and so the suggestion of
a link between the two is not surprising.The
authors propose that the liberation of addi-
tional water from the slab induces further
production of buoyant melt, a necessary
condition ifthe melt is to rise as is seen.
This link to Bercovici and Karato’s model
is intriguing,but I’m not completely sold on
it. Undoubtedly, the argument would be
strengthened by better data on the structure
across the 410-km boundary which, as the
authors point out, is not the best-resolved
feature of the model. Booker et al. suggest
that the mantle to the west of (or beneath)
the slab is dehydrated as a result of melt
extraction at the East Pacific Rise,part ofthe
mid-ocean ridge system in the Pacific Ocean.
Although this might be true for the upper
60–80 km or so of oceanic plate from which
melt and water have been extracted, other
data suggest that there is plenty ofremaining
water that can increase electrical conductivity
in the mantle below about 80 km depth12.
This means that only the region adjacent to
the subducting slab would be expected to be
dry.Ifthere is water around,we would expect
a more or less uniform increase in conduc-
tivity at 410 km across the region.Although
their models show a stepwise increase across
the 410-km boundary, Booker et al. point
out that the data are consistent with a flat
410-km transition throughout the region.
Why is all this important? Well, it speaks to
outstanding issues in terms of resolution of
this critical part ofthe system.
Regardless of the details of the 410-km
boundary,the authors’primary observation
— an electrical conductor that must surely
represent a subduction-related melt column
rising from depth — is striking.And,as they
point out, issues pertaining to the 410-km
boundary and the link to the Bercovici–
Karato hypothesis can be addressed with
measurements made with a longer chain of
MT stations. If the interaction with a melt
layer at 410 km is the explanation,it should
be seen in other subduction systems.It hasn’t
been seen elsewhere yet, but maybe we just
need to look more carefully.
Rob Evans is at Woods Hole Oceanographic
Institution,Woods Hole, Massachusetts 02543, USA.
1. Booker, J. R., Favetto,A. & Pomposiello, M. C. Nature 429,
2. Hirth, G. & Kohlstedt, D. L. Earth Planet. Sci. Lett. 144, 93–108
3. Roberts,J.J.& Tyburczy,J.A. J. Geophys. Res. 104, 7055–7066
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 mito-
chondria must also be made when cells
divide.These events require the replication of
Trifunovic and colleagues wanted to ren-
der 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 muta-
tions 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 age-
ing. To eliminate the proofreading activity,
the authors substituted an alanine amino
acid for a crucial aspartate in the relevant
region ofthe enzyme molecule.
They found that the somatic tissues of
mice bearing two mutant copies of the DNA
polymerase-? gene indeed showed extensive
mitochondrial DNA mutations,largely com-
prising deletions and point mutations. The
percentage of mitochondria bearing dele-
tions was similar in different tissues, and
did not vary with age, suggesting that the
deletions had occurred early in development.
4. Karato, S.Nature 347, 272–273 (1990).
5. Xu,Y. et al. Science 280, 1415–1418 (1998).
6. Wannamaker,P.E.et al. J. Geophys. Res.94, 14127–14144 (1989).
7. Echternacht, F. et al. Phys. Earth Planet. Inter. 102, 69–87
8. Kirby,S. et al. AGU Geophys. Monogr. 96, 195–214 (1996).
9. Hacker,B.R.et al.J.Geophys.Res.108, doi:10.1029/2001JB001129
10.Kay,S.M.& Gordillo,C.E. Contrib. Mineral. Petrol. 117, 25–44
11.Bercovici,D.& Karato,S. Nature 425, 39–44 (2003).
12.Lizarralde, D. et al. J. Geophys. Res. 100, 17837–17854 (1995).
© 2004 Nature PublishingGroup
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NATURE|VOL 429|27 MAY 2004|www.nature.com/nature
The deletions seemed to have converted the
normally circular mitochondrial DNA into
linear molecules, which might not be func-
tional inside cells.
Point mutations were also common;one
mitochondrial enzyme, for instance —
cytochrome b — had a three- to fivefold
increase in single-base substitutions, ran-
domly dispersed throughout the gene. The
mutant animals also showed a decrease in the
activity ofenzymes involved in the respiratory
chain (a crucial series of events in respira-
tion) 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 com-
parable to that seen in ageing humans5.
Strikingly, the mutant mice showed
symptoms consistent with accelerated age-
ing,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 muta-
tions 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 lev-
els of reactive oxygen species and by proton
‘leaks’. Such events can result from muta-
tions in respiratory-chain proteins.
Interestingly, there is a human disease
that might be considered as a parallel to these
mutant mice. Like mouse DNA polymer-
ase-?, 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,progres-
sive external ophthalmoplegia7, which is
characterized by paralysis of the eye muscles
and various effects on other organs, and by
the accumulation of mitochondrial muta-
tions 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 affect-
ed 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 study2establishes that several mani-
festations of ageing in mice can result from
mutations in DNA polymerase-?that induce
error-prone mitochondrial DNA synthesis.
These results do not,however,imply that this
is the only pathway that generates abnorma-
lities resembling ageing. There are several
other DNA-replicating and proofreading
polymerases (?,?and ?) that function in the
nucleus,as well as at least eight newly discov-
ered,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
Of higher priority, however, would be
experiments aimed at finding ways of main-
taining 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.
George M. Martin and Lawrence A. Loeb are in the
Department of Pathology, University of Washington,
Seattle,Washington 98195, USA.
1. Vijg,J. Mutat. Res. 447, 117–135 (2000).
2. Trifunovic,A. et al. Nature 429, 417–423 (2004).
3. Wang,Y. et al. Proc. Natl Acad. Sci. USA 98, 4022–4027 (2001).
4. Melov, S., Hinerfeld, D., Esposito, L. & Wallace, D. C.
Nucleic Acids Res. 25, 974–982 (1997).
5. Nekhaeva,E.et al.Proc.Natl Acad.Sci.USA 99, 5521–5526 (2002).
6. Lim,S.E.,Longley,M.J.& Copeland,W.C. J. Biol. Chem. 274,
7. Agostino,A. et al. Neurology 60, 1354–1356 (2003).
8. Del Bo, R. et al. Neurology 61, 903–908 (2003).
9. Shcherbakova,P.V.,Bebenek,K.& Kunkel,T.A. Science
Sci. Aging Knowledge Environ. doi:10.1126/sageke.2003.8.re3
10.Martin,G.M. Birth Defects Orig. Artic. Ser. 14,5–39 (1978).
Stewart,C.L. Nature 423, 298–301 (2003).
Proc. Natl Acad. Sci. USA 96, 10770–10775 (1999).
13.De Boer, J. et al. Science 296,1276–1279 (2002).
14.Rudolph, K. L.et al. Cell 96, 701–712 (1999).
15.Tyner, S. D. et al. Nature 415, 45–53 (2002).
16.Nabeshima,Y. Ageing Res. Rev. 1, 627–638 (2002).
17.Orsini,F. et al. J. Biol. Chem. doi:10.1074/jbc.M401844200
does today.A famous paradox of ancient cli-
mate demands that we reconcile the persis-
tence of a life-sustaining liquid ocean with
these less-warming rays from a faint young
Sun. The solution lies with greenhouse
gases1, which trap heat near the planet’s
surface.In recent years,methane has become
the favoured greenhouse agent,overcoming
the earlier popularity of carbon dioxide
in climate models spanning most of the
Precambrian eon — that is, during all of
Earth’s history up to about three-quarters
ofa billion years ago,after which life emerged
on a large scale.
On page 395 ofthis issue,Ohmoto and his
colleagues2dispute the arguments against
CO2. Their challenge has additional signifi-
cance because the assertion of inadequate
CO2is the most frequently cited evidence for
the existence of high levels of atmospheric
methane. And given the incompatibility of
methane and oxygen, this debate speaks
more broadly to the oxygenation history of
or the first three-and-a-half billion
years ofEarth’s history,the Sun burned
only about 70–90% as brightly as it
the atmosphere and its link to the evolution
Today, most of us worry about the 30%
rise in levels of CO2 since the Industrial
Revolution and how that may drive global
warming. But a generation of models of
Earth’s atmosphere invoked CO2concentra-
tions as high as a thousand times greater
than those of today to explain the unfrozen
early ocean1.About a decade ago the idea of
CO2as the dominant greenhouse agent was
dealt a blow when Rye and his co-workers3
used the absence of siderite, an iron-rich
carbonate mineral, in ancient soils to set a
maximum for CO2levels in the atmosphere
2.2 billion to 2.75 billion years ago (Fig. 1,
overleaf). This maximum, although still
many times the concentration observed
today,was well below that necessary to offset
the faint young Sun.
Rye et al. were compelled to suggest that
another greenhouse gas — methane — must
have taken up the slack. But their story
was based on only a handful of data and
assumed, among other things, that original
mineral constituents and chemical properties
Warm debate on early climate
Timothy W. Lyons
Would Earth’s early ocean have been a frozen wasteland had levels of
atmospheric methane not been sky high? Maybe. Or maybe, according
to a new view of an old idea, the main warming agent was carbon dioxide.
© 2004 Nature PublishingGroup