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functional consequences in most tissues of old animals. Gustavo Barja de Quiroga
The high level of heteroplasmia of mtDNA, due to the
presence of thousands of mitochondria per cell, and rapamycin decreases mitROSp, or increases autophagy, in
various mtDNA copies per mitochondrion, strongly some but not in all organs at least at the dose used of 14
protects against direct functional effects of mtDNA mg of rapamycin/Kg of diet (121, 139).
mutations. Many copies of mtDNA are present in each
cell. Only if a large majority of these mtDNA copies are The decrease in mitROSp and FRL induced by
mutated, mitochondrial ATP production would be rapamycin treatment in mouse liver occurred together with
compromised. Cells essentially homoplasmic for deleted decreases in the amount of complex I, which contains the
mtDNA are abundant (between 43 and 60 %) in a few ROS generator relevant for aging (see previous sections).
areas like substantia nigra in humans (141, 142), but in the That was associated with an increase (instead of decrease)
brain in general and in other vital tissues of old individuals in mitochondrial biogenesis (139; PGC1a). A possible
their percentage is too low (0.5-2 %) to cause damage explanation of this apparently paradoxical result is that
during aging. rapamycin could selectively induce mitochondrial
biogenesis from the more youthful pool of liver
However, double strand breaks in mtDNA not only can mitochondria. These are expected to show lowered FRL
generate mtDNA deletions. At the same time than they than the more damaged ones. That selection could be
generate deletions, they produce mtDNA fragments, the another reason why rapamycin decreased mitROSp. It has
segments of deleted mtDNA. In agreement with earlier been observed that rapamycin increases autophagy and
proposals (143,144) those fragments can escape from mitochondrial biogenesis in mouse heart suggesting that
mitochondria (145, 146) and are also present inside the damaged mitochondria are replaced by newly synthesized
nucleus (Figures 5B and 7). It was proposed that this could ones to rejuvenate mitochondrial homeostasis. Likely
randomly change nuclear gene information and thereby related to this possibility, it has been observed that DR
contribute to cause cancer and aging (143). It has been (which also inhibits mTOR) and rapamycin both lower
simultaneously demonstrated that these mtDNA fragments mitROSp and FRL and decrease the amount of the "matrix
accumulate inside nDNA with age both in yeast (147) and domain-only" of complex I in the mitochondria of mouse
in rat liver and brain (148), and that such accumulation liver (53). That matrix domain contains the mitROS
causes damage and contributes to aging in yeast (149). generator responsible for the decrease in mitROSp during
Mouse liver also accumulates mtDNA fragments inserted DR (15-18,47,53) and during rapamycin treatment (139).
inside nDNA with age (139). And the dietary treatment
with rapamycin, in addition to decreasing mitROSp, The mtDNA fragments exit from the mitochondria
totally reversed mtDNA fragments accumulation in nDNA towards the nucleus during the lifetime of the individual
(139; Figure 5A,B) and decreased lipofuscin (materials and they insert into nDNA. They are visualized heavily
non-autophagocytosed; Figure 6B) in middle-aged mice. concentrated at the centromeres (Figure 5B, a-c 139).
This last change can be due to a decrease in the presence Thus, the centromeres seem to be the “entry doors” for the
of damaged mitochondria, and/or to the increase in access of mtDNA fragments into chromosomes, perhaps to
autophagy induced by the drug (139, Figure 6A). The be distributed afterwards to other specific chromosome
changes observed for mitROSp and for mtDNA fragments locations at regulatory regions of the master genes
inserted in nDNA are strikingly similar since full(100 %) controlling the "Gene Clusters of Aging" (constituting the
reversion of age related increases occurred in both cases pro-aging program) likely lying in the cell nucleus (see
(Figure 5A,B). This could be due to a cause-effect section 9). The final result would be to promote aging and
relationship between these two parameters, since ROS degenerative diseases including cancer. If that
have strong capacity to produce double strand breaks and phenomenon finally were a regulated one, the initial
then DNA fragmentation. The increase in autophagy and proposal (143) would only be wrong concerning the
the decrease in lipofuscin could also represent a cause- suggested randomness of the process. Random insertion of
effect relationship (Figure 6A,B) although in the case of mtDNA fragments inside nDNA, even if it were restricted
lipofuscin reversion to young levels was only partial. to the structural genes (around 1 % of total nDNA) could
cause cancer (e.g., inserting in, and randomly inactivating
In summary, part of the increase in longevity of tumour suppressor genes) but not aging, because species
rapamycin treated mice can be due to: (i) a decrease in longevity is a tightly regulated species-specific property.
mitROSp; (ii) a decrease in the insertion of mtDNA Further studies are needed to ascertain the random or
fragments inside nDNA; and (iii) an increase in regulated character of mtDNA fragments insertion into
autophagy. Interestingly, in a parallel experiment we did nDNA starting at the centromeres.
not detect significant changes in mitROSp in the heart
after the rapamycin treatment. Therefore, the reason why Migration of mtDNA fragments from mitochondria to
rapamycin increases life span to a much lower extent (11 nucleus is strongly reminiscent of what happened during
% increase in maximum lifespan) than DR (up to 40 % millions of years of evolution after the symbiogenesis
increase) can be due to the impact of DR on more event that created the Eukaryotic cell around 2.000 million
longevity signaling pathways than those involving mTOR years ago. During such evolution most genes of the
(Figure 8). But it can also be due to the possibility that initially free living Rickettsia-like a-proteobacteria were
transferred to what is now the nuclear genome of the
66 eukaryotic cell. This would constitute a further example of
the old observation that in various cases “ontogeny
@Real Academia Nacional de Farmacia. Spain
