Poor old pores—The challenge of making and maintaining nuclear pore complexes in aging

Abstract

The nuclear pore complex (NPC) is the sole gateway to the nuclear interior, and its function is essential to all eukaryotic life. Controlling the functionality of NPCs is a tremendous challenge for cells. Firstly, NPCs are large structures, and their complex assembly does occasionally go awry. Secondly, once assembled, some components of the NPC persist for an extremely long time and, as a result, are susceptible to accumulate damage. Lastly, a significant proportion of the NPC is composed of intrinsically disordered proteins that are prone to aggregation. In this review, we summarize how the quality of NPCs is guarded in young cells and discuss the current knowledge on the fate of NPCs during normal aging in different tissues and organisms. We discuss the extent to which current data supports a hypothesis that NPCs are poorly maintained during aging of nondividing cells, while in dividing cells the main challenge is related to the assembly of new NPCs. Our survey of current knowledge points toward NPC quality control as an important node in aging of both dividing and nondividing cells. Here, the loss of protein homeostasis during aging is central and the NPC appears to both be impacted by, and to drive, this process.

DNA circles promote yeast ageing in part through stimulating the reorganization of nuclear pore complexes

“…Still, proteomics analysis of the old yeast cells indicate that they progressively change composition, losing their nuclear basket and cytoplasmic complexes ( Janssens et al, 2015 ; Rempel et al, 2019 ). Similar changes are observed in the liver of ageing rats ( Ori et al, 2015 ; Rempel et al, 2020 ). However, little is known about how age drives these changes and whether this process is simply a consequence or contributes to ageing.…”

“…From yeast to mammals, nuclear pore complexes (NPCs), which mediate transport of cargos between nucleus and cytoplasm, undergo substantial changes during ageing ( Rempel et al, 2020 ). In post-mitotic cells such as neurons, core NPC components do not turnover, tend to become oxidized over time and progressively lose functionality ( Savas et al, 2012 ; Toyama et al, 2013 ).…”

Changes in DNA double-strand break repair during aging correlate with an increase in genomic mutations

“…Work performed in human and yeast have linked nuclear architecture with aging and genome stability pathways (Lans & Hoeijmakers 2006; Kubben & Misteli 2017). Naturally aged yeast showed an increase in nuclear envelope herniations associated with NPC regions and a decline in NPC assembly (Janssens & Veenhoff 2016; Rempel et al 2020). The stability of the genome relies on the sequestration and compartmentalization of irreparable DSBs at the nuclear periphery, to environments conducive to repair.…”

Specialization of chromatin-bound nuclear pore complexes promotes yeast aging

“…Still, proteomics analysis of the old yeast cells indicate that they progressively change composition, losing their nuclear basket and cytoplasmic complexes (Janssens et al, 2015;Rempel et al, 2019). Similar changes are observed in the liver of aging rats (Ori et al, 2015;Rempel et al, 2020). However, little is known about the underlying mechanisms and whether this process is simply a consequence or contributes to aging.…”

“…Nuclear pore complexes (NPCs), which mediate transport of cargos between the nucleus and the cytoplasm, undergo substantial changes during aging from yeast to mammals (Rempel et al, 2020). In post-mitotic cells such as neurons, core NPC components are very stable, tend to become oxidized over time and progressively lose functionality (Savas et al, 2012;Toyama et al, 2013).…”