Modeling the Role of Mitochondrial Mutations in Cellular Aging

Summary: Model of what happens if mitochondria with damaged DNA both reproduces and degrades slower than intact mitochondria, and how it fits observed data

Interestingness: 7

Paper by Axel Kowald and Thomas BL Kirkwood in the Journal of Anti-Aging Medicine, Volume 2, Issue 3, Fall 1999.

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They start by claiming there is a problem with the then-present theory of how damaged mitochondria are preferentially disseminated/take over cells by noting that it, the theory, is inconsistent with experimental results that show that damaged mitochondria is more prevalent in senescent cells than in dividing cells, and that the cells, or at least the muscle fibres, are taken over by one mutant type of mitochondria (by one I mean one type per case, not one common type for all cases) like we just saw in the last post http://readingrejuvenationresearch.blogspot.com/2010/12/segmental-nature-of-age-associated.html. Those are the main problems they want to see if they can patch with their model.

Their model starts at de Grey's model http://readingrejuvenationresearch.blogspot.com/2010/01/proposed-refinement-of-mitochondrial.html that basically hypothesises that mutant mitochondria produce less holes in their membranes and so are degraded less often. They justify the apparent contradiction in mutant mitochondria producing less holes with the "well known" fact that they produce more radicals by saying that most radicals are O2.- radicals but only the perhydroxy radical (HO2.-) can rip protons from lipids. Mutant mitochondria have a lower proton gradient so they produce lower amounts of HO2.- even if they produce more O2.-. Would seem good to get actual measurements, but they say that these aren't available and that they would be hard to get.

They, instead, produce a model with two assumptions: the first is that damaged mitochondria are destroyed slower than ones with intact mtDNA, and secondly, one introduced by them, that damaged mitochondria grow slower, which they justify by the energy shortage produced by the lower proton gradient. They split mitochondria into six groups, for little membrane damage, medium membrane damage and high membrane damage, each with intact mtDNA or mutant mtDNA. Radicals can increase the level of membrane damage or switch the mitochondria from an intact to a damaged mtDNA state. They give different turnover rates for mitochondria in each of the membrane damage classes, independent of their mtDNA state. The corresponding half lives for each damage class are 10, 2 and 1 week for low, medium and high damage. They used a factor of 2 as the increase in rate of free radicals that a mutant mitochondria produces compared to intact mitochondria, that mutants produced membrane damage at a rate 10 times lower than intact, and that intact grew 5 times quicker. I guess these numbers were half-guesses, and probably important in the results they got.

The model replicates the features from experiments they were looking to replicate, with one mutant taking over cells, and senescent cells having larger proportion of mutants than dividing cells, due to cell replication being a purifier of mitochondria. This purification happens because of the growth advantage of the intact mitochondria. This effect dominates when large amounts of mitochondria are to be produced, as in dividing cells, but the rate of destruction dominates when few mitochondria are being synthesised. They have some graphs showing what happens when the parameters are very different: if the mitochondria destruction rate are a bit lower, the population eventually collapses, if they are much higher, they collapse very quickly, along with other graphs showing the effects of different rates of cell reproduction and how that affects mitochondria population and stability (quick enough cell reproduction can fix higher rates of mutation).

From the model they also predict differences in importance between telomere shortening and mitochondrial damage in vivo vs in vitro. They claim that because in vitro conditions cells are replicated quickly, their collection of mitochondria will be pure through the process talked about above, so they will reach their Hayflick limit with nary an issue in their mitochondria, while in vivo, where cells replicate more slowly, mitochondrial damage will accumulate earlier and keeping telomeres long will not have an effect on cell lifespan.

(Interesting little factoid in the paper that I didn't fit in anywhere else: oxygen radicals are estimated to amount to 1-4% of consumed oxygen which sounded like a lot)

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Abstract follows:

The mitochondrial theory of aging suggests that an accumulation of defective mitochondria leads to loss of cell viability. The challenge is to explain how mitochondrial defects accumulate within cells, and why this process is more evident in postmitotic than in dividing cells. We describe a new mathematical model incorporating two critical features: (a) defective mitochondria are turned over more slowly than intact ones, and (b) defective mitochondria suffer a growth disadvantage. We also model the effect of cell division on the accumulation of defective mitochondria. The results support the mitochondrial theory and explain many of the observed data. The relationship of the mitochondrial theory to the suggested role of telomere loss in cell replicative senescence is discussed. We suggest that because of differences in the kinetics of their impact on cells, these two mechanisms have different relative importance for in vivo and in vitro cell aging.