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Altering nuclear pore complex function impacts longevity and mitochondrial function in S. cerevisiae.

Lord CL, Timney BL, Rout MP, Wente SR - J. Cell Biol. (2015)

Bottom Line: Mutants lacking the GLFG domain of Nup116 displayed decreased RLSs, whereas longevity was increased in nup100- mutants.Both Kap121-dependent transport and Nup116 levels decrease in replicatively aged yeast.Together, these studies reveal that specific NPC nuclear transport events directly influence aging.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232.

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NPCs regulate RLS by influencing specific nuclear transport pathways. Functional NPCs in young wild-type cells properly mediate Kap121-dependent nuclear import. Degradation or loss of Nup116 and Nsp1 causes deterioration of NPC function in replicatively aged wild-type cells, which inhibits nucleocytoplasmic transport and likely increases NPC permeability. Along with other signaling pathways that regulate longevity, inhibited Kap121 transport decreases mitochondrial membrane potential and reduces RLS. Mitochondrial membrane potential is similar to wild type in young nup116ΔGLFG nup145ΔGLFG cells but is reduced faster during the aging process because Kap121-dependent transport is inhibited in young cells. Accelerated reduction in membrane potential is likely at least partially responsible for the decreased RLSs of nup116ΔGLFG nup145ΔGLFG cells.
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fig7: NPCs regulate RLS by influencing specific nuclear transport pathways. Functional NPCs in young wild-type cells properly mediate Kap121-dependent nuclear import. Degradation or loss of Nup116 and Nsp1 causes deterioration of NPC function in replicatively aged wild-type cells, which inhibits nucleocytoplasmic transport and likely increases NPC permeability. Along with other signaling pathways that regulate longevity, inhibited Kap121 transport decreases mitochondrial membrane potential and reduces RLS. Mitochondrial membrane potential is similar to wild type in young nup116ΔGLFG nup145ΔGLFG cells but is reduced faster during the aging process because Kap121-dependent transport is inhibited in young cells. Accelerated reduction in membrane potential is likely at least partially responsible for the decreased RLSs of nup116ΔGLFG nup145ΔGLFG cells.

Mentions: Our results are consistent with a model whereby NPC damage contributes to the aging process in wild-type cells (Fig. 7). Replicatively aged NPCs likely contain partially degraded Nups because full-length Nup116 and Nsp1 levels are decreased in aged cells (Fig. 3 B), even though Nsp1-GFP still localizes to the nuclear rim (Fig. 3 D). Loss of Nup116’s GLFG domain then inhibits Kap121-dependent nuclear import (Fig. 2 B), which compromises mitochondrial function (Figs. 5 and 6) and decreases RLS (Figs. 1 A and 2 D). We speculate that deletion of Nup116’s GLFG domain promotes aging because Kap121-mediated transport is inhibited in young cells, limiting the function of their mitochondria and replicative potential during the aging process. RLS is further reduced in nup116ΔGLFG nup145ΔGLFG cells because of functional redundancy between the GLFG domains of Nup145 and Nup116 (Fig. 1 A). Overexpression of GSP1 suppresses mitochondrial defects in nup116ΔGLFG cells and thus extends the RLS in mutant cells. We hypothesize that GSP1 overexpression increases RLS in wild-type cells by limiting some of the nuclear transport defects observed in aged cells.


Altering nuclear pore complex function impacts longevity and mitochondrial function in S. cerevisiae.

Lord CL, Timney BL, Rout MP, Wente SR - J. Cell Biol. (2015)

NPCs regulate RLS by influencing specific nuclear transport pathways. Functional NPCs in young wild-type cells properly mediate Kap121-dependent nuclear import. Degradation or loss of Nup116 and Nsp1 causes deterioration of NPC function in replicatively aged wild-type cells, which inhibits nucleocytoplasmic transport and likely increases NPC permeability. Along with other signaling pathways that regulate longevity, inhibited Kap121 transport decreases mitochondrial membrane potential and reduces RLS. Mitochondrial membrane potential is similar to wild type in young nup116ΔGLFG nup145ΔGLFG cells but is reduced faster during the aging process because Kap121-dependent transport is inhibited in young cells. Accelerated reduction in membrane potential is likely at least partially responsible for the decreased RLSs of nup116ΔGLFG nup145ΔGLFG cells.
© Copyright Policy - openaccess
Related In: Results  -  Collection

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fig7: NPCs regulate RLS by influencing specific nuclear transport pathways. Functional NPCs in young wild-type cells properly mediate Kap121-dependent nuclear import. Degradation or loss of Nup116 and Nsp1 causes deterioration of NPC function in replicatively aged wild-type cells, which inhibits nucleocytoplasmic transport and likely increases NPC permeability. Along with other signaling pathways that regulate longevity, inhibited Kap121 transport decreases mitochondrial membrane potential and reduces RLS. Mitochondrial membrane potential is similar to wild type in young nup116ΔGLFG nup145ΔGLFG cells but is reduced faster during the aging process because Kap121-dependent transport is inhibited in young cells. Accelerated reduction in membrane potential is likely at least partially responsible for the decreased RLSs of nup116ΔGLFG nup145ΔGLFG cells.
Mentions: Our results are consistent with a model whereby NPC damage contributes to the aging process in wild-type cells (Fig. 7). Replicatively aged NPCs likely contain partially degraded Nups because full-length Nup116 and Nsp1 levels are decreased in aged cells (Fig. 3 B), even though Nsp1-GFP still localizes to the nuclear rim (Fig. 3 D). Loss of Nup116’s GLFG domain then inhibits Kap121-dependent nuclear import (Fig. 2 B), which compromises mitochondrial function (Figs. 5 and 6) and decreases RLS (Figs. 1 A and 2 D). We speculate that deletion of Nup116’s GLFG domain promotes aging because Kap121-mediated transport is inhibited in young cells, limiting the function of their mitochondria and replicative potential during the aging process. RLS is further reduced in nup116ΔGLFG nup145ΔGLFG cells because of functional redundancy between the GLFG domains of Nup145 and Nup116 (Fig. 1 A). Overexpression of GSP1 suppresses mitochondrial defects in nup116ΔGLFG cells and thus extends the RLS in mutant cells. We hypothesize that GSP1 overexpression increases RLS in wild-type cells by limiting some of the nuclear transport defects observed in aged cells.

Bottom Line: Mutants lacking the GLFG domain of Nup116 displayed decreased RLSs, whereas longevity was increased in nup100- mutants.Both Kap121-dependent transport and Nup116 levels decrease in replicatively aged yeast.Together, these studies reveal that specific NPC nuclear transport events directly influence aging.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232.

Show MeSH