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Cellular incontinence: In postmitotic cells, nuclear pores become leaky with age

Posted Mar 03 2009 2:17pm

How do cells get rid of their garbage? One solution is simply to outgrow it: if the rate of synthesis of new components exceeds the rate of accumulation of old ones, then unwanted trash will be diluted out, even without any active clearance. This is only really possible in exponentially growing populations, however: slowly dividing or postmitotic cells must activate degradative pathways (e.g., autophagy and ubiquitin-proteasome) in order to prevent accumulation of potentially toxic damaged macromolecules and dysfunctional organelles.

In order to degrade a protein, protein complex or organelle, however, one must first be able to get at it — and there are specific cellular components that make this very difficult. As an example, let’s consider the nuclear pore complex (NPC): it’s huge (120 megaDaltons), complex (>30 protein components) and topologically challenging (the pore crosses the nuclear envelope and creates a hole in the process). Many NPC components aren’t in dynamic equilibrium with cytosolic pools, so if we want to turn over any of these proteins we would have to somehow take out the entire NPC, repair the ensuing damage to the membrane, and then either re-insert the NPC (which I don’t believe actually happens) or synthesize a new NPC to restore the lost import/export capacity.

Unfortunately, new nuclear pores are probably only created during mitosis, when the nuclear envelope and topologically connected endoplasmic reticulum (ER) split up into vesicles that subsequently re-fuse after cell division is complete. So how do postmitotic cells turn over and degrade NPCs?

The answer, according to D’Angelo et al., is that they probably don’t. Instead, NPCs get old, and accumulate damage, and eventually stop doing their job:

Age-Dependent Deterioration of Nuclear Pore Complexes Causes a Loss of Nuclear Integrity in Postmitotic Cells

In dividing cells, nuclear pore complexes (NPCs) disassemble during mitosis and reassemble into the newly forming nuclei. However, the fate of nuclear pores in postmitotic cells is unknown. Here, we show that NPCs, unlike other nuclear structures, do not turn over in differentiated cells. While a subset of NPC components, like Nup153 and Nup50, are continuously exchanged, scaffold nucleoporins, like the Nup107/160 complex, are extremely long-lived and remain incorporated in the nuclear membrane during the entire cellular life span. Besides the lack of nucleoporin expression and NPC turnover, we discovered an age-related deterioration of NPCs, leading to an increase in nuclear permeability and the leaking of cytoplasmic proteins into the nucleus. Our finding that nuclear leakiness is dramatically accelerated during aging and that a subset of nucleoporins is oxidatively damaged in old cells suggests that the accumulation of damage at the NPC might be a crucial aging event.

The damaged NPCs are no longer effective at actively segregating cytosolic and nuclear proteins; the resulting “leakiness” exemplifies the general principle of age-related loss of fidelity. This leakiness could be causally connected to aging in several different ways: components targeted to the wrong compartment could have deleterious consequences in their new homes; damaged NPCs could distort the nuclear envelope in a manner analogous to the effect of lamin mutations; or a combination of these and other effects could contribute to the transcriptional dysregulation that has been observed in multiple cell types and experimental systems.

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