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Mitochondrial ROS and mtDNA fragments inside nuclear DNA as a main effector of ageing: the “cell aging regulation system”

The inverse nature of the changes induced by rapamycin in both parameters suggest a cause-effect relationship between the increase in
autophagy and the partial reversal of lipofuscin accumulation. Modified from ref. 139.

8. mtDNA FRAGMENTS INSIDE NUCLEAR DNA lifespan of a single individual, they can not be responsible
AND AGING for the strongly different longevity of the different species
nor for the change in longevity induced by the different
A further complication is the possibility that kinds o DRs, since these longevities are genetically,
mitochondrial ROS-derived damage affects aging genes instead of randomly, controlled. In other words, there is no
back in the nucleus through the insertion of mtDNA plausible mechanisms that would lead rats to commit 30
fragments inside nDNA (Figures 5B and 7). fold more errors than humans during mtDNA replication
or repair. Replication and repair as source of mtDNA
Oxidative damage to mtDNA bases, like 8-oxodG, is mutations suffers the same limitation that many other
also repaired in the mitochondria. But mitROS, in addition wrong proposals based on random processes (e.g. wear and
to DNA base and sugar oxidative modifications, have the tear theories of aging). Instead, the longevity of a species,
capacity to produce double strand breaks in DNA in or fine tuning of longevity to a new level in DR, is
general, and with more reason in the very nearby situated determined by the genotype. Then, it must necessarily be
mtDNA. Fragmentation of mtDNA through double strand due to the existence of genetically programmed processes
breaks by the nearby generated mitROS can be one cause residing in the cell nucleus which can respond to
of the well known accumulation of mtDNA mutations, environmental nutrient availability (during DRs) with
including large mtDNA deletions, with age (140).
Recently, it has been proposed that mtDNA mutations can appropriate changes in longevity (see section 9).
also be due to errors during DNA replication and repair,

rather than to mitROSp. However, while those random

errors can contribute to accumulated damage during the

Figure 7 mtROSp and mtDNA fragments inside nuclear DNA. mtROS produced at Cx I generators (stars) cause damage in the mtDNA
situated nearby or even in contact with the complex I site of ROS production. This causes, in addition to oxidized bases, double strand
breaks leading to large deletions and, most importantly, also mtDNA fragments. These exit the mitochondria and insert into nuclear DNA at the
centromeres during aging in yeast, rats and mice, and contribute to aging. This is reminiscent of what happened during evolution after the

symbiogenesis of the eukaryotic cell from a-proteobacteria and Archea around 2.000 million years ago. Rapamycin treatment decreases such
mtDNA fragment accumulation in the liver of middle aged mice (Figure 5B; Refs. 139,143-149).

The occurrence of large mtDNA deletions, which lack of many genes coding for electron transport chain or
increase with age in mammalian tissues, has been mitochondrial ribosome subunits in a single mtDNA circle
proposed as one final detrimental effect causing aging. molecule. However it is now clear that, with the exception
Since mtDNA is highly compacted, without introns, the of a few tissues, the level of these deletions does not reach
large deletions detected in old tissues would lead to the the threshold needed, in homoplasmia, to be of negative

@Real Academia Nacional de Farmacia. Spain 65