I’ll never be like you: Daughter cells send toxic aggregates back to mom

Cells tend to produce unwanted protein aggregates and other molecular refuse slightly faster than they can get rid of it, resulting in a time-dependent accumulation of potentially toxic cellular garbage. This, in turn, can cause an age-dependent loss of cellular viability, which is (in certain contexts) a fair operational definition of aging.

How can cells deal with their garbage? Protein aggregates are both sticky and insoluble, making it hard for cellular machinery to deal with them at an enzymatic level. If the gunk can’t be eliminated, however, it might still be possible to move it around in a useful way. Specifically, at mitosis, the cell could make sure that all the potentially toxic aggregates stay in one of the progeny. To illustrate the argument I’ll turn to the words of the estimable Alex Palazzo:

One approach is to distribute everything equally amongst your two offspring. …

A second approach is to give all the crap to one of the two new cells and keep the other one pristine. Lets call these two cells the crap cell and the pristine cell. What’s the result of this second strategy? Using our crap metric from above, the first cell accumulates 10 units of garbage over its lifetime and then gives it all to one offspring, the crap cell, and none to the other offspring, the pristine cell. Those cells then grow and by the time they divide each second generation cells have made 10 units of additional crap each. The crap cell has 20 units the pristine cell 10. The two cells divide and dump all their garbage on one of their offsprings. One cell starts with 20 units of crap, one cell with 10 units and two cells are again crap free. The end result of this strategy? Part of your descendents will become more and more decrepit as they fill up with crap, while others remain pristine.

The crap cell (I love this nomenclature) will become inviable sooner under this strategy, but the alternative would be a symmetric division strategy in which all descendants accumulate garbage, ultimately causing the extinction of the entire lineage. The idea here is that assuming certain values for adjustable parameters re: the rate of garbage accumulation and the effect of garbage level on reproductive fitness, this can be an advantageous strategy to ensure reproductive success. Both single-celled yeast and mammalian stem cells employ this asymmetric strategy in order to preserve the viability of an indefinitely dividing lineage.

In yeast, the crap cell is called the “mother”; the pristine cell is called the “daughter” — mom accumulates garbage of various kinds, both protein aggregates and rDNA circles. When the mother is ready to divide, a bud forms at a specific site on her cell wall, defined by a set of macromolecular complexes that determine cellular polarity. Liu et al. have demonstrated that the daughter cell is using some of the same polarity-determining machinery (the “polarisome”) to actively transport protein aggregates back into the mother:

The Polarisome Is Required for Segregation and Retrograde Transport of Protein Aggregates

The paradigm sirtuin, Sir2p, of budding yeast is required for establishing cellular age asymmetry, which includes the retention of damaged and aggregated proteins in mother cells. By establishing the global genetic interaction network of SIR2 we identified the polarisome, the formin Bni1p, and myosin motor protein Myo2p as essential components of the machinery segregating protein aggregates during mitotic cytokinesis. Moreover, we found that daughter cells can clear themselves of damage by a polarisome- and tropomyosin-dependent polarized flow of aggregates into the mother cell compartment. The role of Sir2p in cytoskeletal functions and polarity is linked to the CCT chaperonin in sir2Δ cells being compromised in folding actin. We discuss the findings in view of recent models hypothesizing that polarity may have evolved to avoid clonal senescence by establishing an aging (soma-like) and rejuvenated (germ-like) lineage.

Note the role for Sir2p, the founding member of the sirtuin family of longevity assurance genes: Sir2p is required, via another protein’s activity, for the normal folding of actin, the cytoskeletal protein from which the daughter-mother transport cable is built. It’s an indirect interaction, and more complex than I’m making it out to be here. Nonetheless, it is satisfying for those of us looking for unifying theories in aging that one of the most widely studied proteins in lifespan regulation is involved in the deep connection between polarity and aging.

I’ll close with a few questions:

  • Why can’t the mother cell export the aggregates? One of our initial premises was that aggregates are biochemically hard to handle, which is why they accumulate rather than being degraded. But now we know that cells can bundle aggregates onto actin cables and move them around — why not sort the aggregates into vesicles or membrane blebs and dispose of them? Granted, in order to export an aggregate out of the cell, it would have to cross a membrane, but this would be no more difficult topologically than mitophagy. The obvious (and trivial) answer to this question is “because it didn’t evolve that way,” but I’m curious to know whether there’s some compelling reason why it couldn’t have evolved that way.
  • How do symmetrically dividing cells overcome this problem? In order to exploit asymmetric division, one must first establish polarity. The argument above about the rate of garbage accumulation would seem to apply equally well to non-polarized cells like bacteria – why, then, do clonal lineages of symmetrically dividing cells not invariably go extinct? Maybe the cells that we think are symmetric are secretly asymmetric, with a crap/pristine segregation that has yet to be uncovered. Or maybe the symmetric cells know something about garbage disposal that we don’t. In either case, there’s something important to learn that might help us keep mammalian cells youthful.

ResearchBlogging.orgLiu, B., Larsson, L., Caballero, A., Hao, X., Öling, D., Grantham, J., & Nyström, T. (2010). The Polarisome Is Required for Segregation and Retrograde Transport of Protein Aggregates Cell, 140 (2), 257-267 DOI: 10.1016/j.cell.2009.12.031

Advertisements

5 comments

  1. As regards your question “why not sort the aggregates into vesicles or membrane blebs and dispose of them?” This might just be ignorance on my fault but I have never heard of *any* cells that package away bits of themselves and simply let them loose.

    Creating membranes, and even aggregates, takes a lot of energy and effort, and cells tend to be reluctant to let parts of themselves go, even if those parts may be potentially harmless. Bacteria will export toxins, but they never packege them away in little membranes and bleb them off.

  2. Cells eject parts of themselves all the time, q.v. microvesicles.

    Membrane might be expensive, but so is losing clonal viability. A cell might be willing to part with a bit of material in exchange for a longer replicative life. (The expense of making aggregates is irrelevant here; the cell never gets to use that material again in any case, so it’s wasted regardless.)

    Another solution to the problem would be to envelop the aggregates in a membrane which then fuse with the plasma membrane, ejecting the toxic aggregates while allowing recovery of the membrane itself.

    Again, I get that this doesn’t happen – my point was that there’s a potentially effective solution that evolution apparently never stumbled across.

  3. I’m somewhat reluctant to sound like I’m repackaging what Lab Rat said, but evolution is often a slave to energetics. What would be the energetic cost of periodically shedding a piece of every cell in your body for the sake of removing toxins? Also, what about complex organisms? Take humans for example – if our cells would shed toxic exosomes every so often, where would they go? Would other cells then have to actively transport them across boundaries and junctions in order to get them to a place where they could finally be excreted by the body? Active transport is another fairly energetic process. Certainly the exosomes or discarded loose toxins can’t just sit in the extracellular space. Photoreceptors and retinal pigment epithelial cells do that when the RPE can’t keep up metabolically, and henceforth comes retinal degeneration.

    Re: Symmetric cells … You got me there.

  4. Right, but if the cost of not doing it is that you lose clonal viability, then it could make sense to spend that energy.

    It would be dumb to do it haphazardly (i.e., shedding mass on the mad hope that an aggregate happened to be in that particular parcel of cytoplasm) but smart to do it using specific machinery that can identify the aggregates. The active transport reported in the paper shows that identification and specific handling of aggregates is already solved.

    The point about where the toxic exosomes would go within a body is a very good one, so that is a great answer for why this would be a bad solution in metazoans. Still not convinced it couldn’t work for free-living single cells.

  5. Glad you covered the paper.

    I agree that it is weird that cells do not eject these potentially cytotoxic aggregates, however there may be some other items that can never be disposed of. There’s quite a bit of evidence (including a new paper in Science) that links DNA microsatellite formation and aging. There it is quite a bit of evidence that the mother (aka crap) cell inherits all the severely damaged DNA, including microsatellite DNA. These small DNA fragments will not be so easy to get rid of – how would you identify them? How could you dispose of this without creating a whole new set of macromolecular machines? Another problem is the cell wall, with every new bud that is produced from the mother, the cell wall gets damaged. In fact each time a mother forms a buds, it does so a new site. Eventually the mother runs out of “bud sites”.

    So the mother will become crap, no matter what, and it is probably better off spending its energy making more pristine cells rather than decrap-ifying itself. After all, the act of dividing, in a sense is the ultimate way to get rid of all the crap (+damaged DNA, +damaged cell wall).

Comments are closed.