Mitochondria in certain tissues are known to accumulate high levels of one and the same (= clonal) deletion. Several hypotheses have been postulated that can explain this accumulation - replication advantage, "survival of the slowest"and drift - but empirical evidence for these models has been lacking. Now the Aiken and McKenzie lab has considerably strengthened the replication advantage angle by showing a vicious circle that operates in vivo by promoting mitochondrial DNA replication. On the other hand, modeling by Kirkwood, Kowald and others (2, 3) further confirms that drift and size based replication advantage in and of themselves, and without any vicious feedback loops, operate too slowly to explain aging in short-lived species like mice.
Now, based on these three studies (1-3) we can propose a basic model for deletion accumulation that, as far as I can tell, is consistent with published data: Drift and replication advantage lead to an accumulation of OXPHOS-deficient, deletion-bearing mtDNAs until a critical threshold is reached. Then, the cell tries to compensate. Drift + Replication Advantage + Feedback Loop = fast accumulation of deletions. Aiken et al. call this feedback loop "non-adaptive program of mitochondrial biogenesis" or vicious cycle.
Two compensatory mechanisms could be maladaptive in this situation and a trigger of this vicious cycle:
1. PGC1-alpha and other proteins induce mtDNA replication (1). Thus increasing the advantage enjoyed by deletion bearing genomes. The explanation is, simply put, that the shorter an mtDNA mutant genome, the earlier it will stop replicating and then it will be able to replicate again.
Aiken et al. put it this way:
The coordinate up-regulation of mitochondrial DNA polymerase gamma and PEO1, the mitochondrial helicase twinkle in ETS abnormal fibers (Table S1), provides a coherent explanation for the expansion of mitochondrial genomes as over-expression of these two proteins is sufficient for mitochondrial genome proliferation in vivo . The activation of AMP kinase suggests that accumulation of AMP initiates signaling for mitochondrial biogenesis and metabolic processes. The loss of β-oxidation would allow for the accumulation of long-chain fatty acids, potent endogenous pparα agonists. Further the expression of pgc-1α is a known inducer of mitochondrial biogenesis. The cellular response to the lack of mitochondrial electron transport and oxidative phosphorylation attempts to correct the defect by up-regulating genes responsible for mitochondrial DNA replication and metabolism. This response is non-adaptive and stimulates further deletion mutation accumulation through the expression of polymerase γ and PEO1/twinkle, expanding the cellular defect.2. Low ATP production leads to AMPK stimulation (1) and presumably autophagy induction. This shortens the mtDNA half-life, which would greatly increase the replication advantage of small genomes - unless preferential mitophagy completely offsets this kinetic advantage. Models suggest that a change in half-life from 10 to 2 days would accelerate deletion accumulation by around x25 (2). However, the data on mitochondrial DNA half-lives is problematic and possibly unreliable according to the authors of (2).
The compensatory mechanism discovered by the Aiken and McKenzie group solves the kinetic problem, at least qualitatively. Until now, no proposed mechanism was fast enough to explain accumulation of deletions in species shorter-lived than humans (2, 3). Whether the numbers add up in reality, is a different question and must be demonstrated experimentally and via modeling.
A connection to other studies?
I was a little surprised to find out that a similar effect has been documented in vitro, because Aiken et al. never mention such studies. However, a review from 2007 (7) asserts that:
[Kearns-Sayre] is unique in that the responsible mtDNA aberration involves deletions rather than point mutations. Kearns-Sayre cybrid work has resulted in two notable observations (Tang et al., 2000). The first is that large mtDNA deletions but not duplications seem to result in mitochondrial respiratory failure. The second is that rather than attempt to maintain a constant mtDNA copy number, osteosarcoma cybrid cells rather prefer to maintain a constant amount of mtDNA. In other words, when osteosarcoma cells are populated predominantly by mtDNA with large deletions, the mtDNA copy number increases to such an extent the amount of mtDNA approximates the amount of mtDNA in cybrid cells without mtDNA deletions.The underlying mechanism clearly could be very similar to the phenomenon demonstrated by Aiken.
On a different note: a recent paper found that, contrary to expectations, activation of the anabolic and anti-proteolytic Akt pathway was harmful to muscle during aging (4). Understandably the authors link this to protein degradation: "sarcopenia is accelerated, not delayed, when protein degradation pathways are impaired."
And of course, the result is not completely contrary to our knowledge. Autophagic and proteolytic turnover has been know to be vital to tissue maintenance for some time and mTOR inhibition (and resulting catabolism) recently has been linked to slowed aging.
Based on the data by Aiken there is another reading of the paper by Sandri et al. Akt stimulation activated mTOR, as is commonly known, which then stimulated mitochondrial biogenesis (see ref. 5a for in vitro data) and promoted a vicious cycle. This does not mean that we have to rule out the impact of autophagy/proteolysis, however.
One problem remains: how do we explain species specific aging rate?
This mechanisms shows that mutations can in principle accumulate at a rate consistent with naturally observed lifespans. However, it does not explain by which mechanism the rate of accumulation differs between species.
Given the strength of this hypothesis it is time to test it in vivo. A method to accelerate deletion accumulation already exists (PGC1-a induction) and presumably rapamycin may be used to slow accumulation. The missing link is a study that shows decreased and increased muscle function, respectively, after each of those treatments started during adulthood or even middle age.
Furthermore, the work by Swerdlow demonstrates that an in vitro model of this "non-compensatory program of mitochondrial biogenesis" may be possible.
1. PLoS One. 2013;8(3):e59006. doi: 10.1371/journal.pone.0059006. Epub 2013 Mar 13. Mitochondrial biogenesis drives a vicious cycle of metabolic insufficiency and mitochondrial DNA deletion mutation accumulation in aged rat skeletal muscle fibers. Herbst A, Johnson CJ, Hynes K, McKenzie D, Aiken JM.
2. J Theor Biol. 2013 Sep 17;340C:111-118. doi: 10.1016/j.jtbi.2013.09.009. [Epub ahead of print] Mitochondrial mutations and ageing: Can mitochondrial deletion mutants accumulate via a size based replication advantage? Kowald A, Dawson M, Kirkwood TB.
3. Aging Cell. 2013 Aug;12(4):728-31. doi: 10.1111/acel.12098. Epub 2013 Jun 7.
Mitochondrial mutations and aging: random drift is insufficient to explain the accumulation of mitochondrial deletion mutants in short-lived animals.
Kowald A, Kirkwood TB.
4. Biogerontology. 2013 Jun;14(3):303-23. doi: 10.1007/s10522-013-9432-9. Epub 2013 May 19.
Signalling pathways regulating muscle mass in ageing skeletal muscle: the role of the IGF1-Akt-mTOR-FoxO pathway.
Sandri M, Barberi L, Bijlsma AY, Blaauw B, Dyar KA, Milan G, Mammucari C, Meskers CG, Pallafacchina G, Paoli A, Pion D, Roceri M, Romanello V, Serrano AL, Toniolo L, Larsson L, Maier AB, Muñoz-Cánoves P, Musarò A, Pende M, Reggiani C, Rizzuto R, Schiaffino S.
5a. Cell Metab. 2013 Nov 5;18(5):698-711. doi: 10.1016/j.cmet.2013.10.001.
mTORC1 controls mitochondrial activity and biogenesis through 4E-BP-dependent translational regulation.
Morita M, Gravel SP, Chénard V, Sikström K, Zheng L, Alain T, Gandin V, Avizonis D, Arguello M, Zakaria C, McLaughlan S, Nouet Y, Pause A, Pollak M, Gottlieb E, Larsson O, St-Pierre J, Topisirovic I, Sonenberg N.
and this seems to be partially replicated in vivo: 5.b. http://biomedgerontology.oxfordjournals.org/content/early/2013/05/04/gerona.glt047.short
6. J Neurosci Res. 2007 Nov 15;85(15):3416-28.
Mitochondria in cybrids containing mtDNA from persons with mitochondriopathies.