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

Christopher L Lord1, Benjamin L Timney2, Michael P Rout2

  • 1Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232.

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Specific nuclear pore complex proteins and transport events regulate aging and longevity in yeast, independent of nuclear permeability. These findings highlight novel roles for nucleocytoplasmic transport in the aging process.

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Area of Science:

  • Cell Biology
  • Aging Research
  • Molecular Genetics

Background:

  • Nuclear pore complexes (NPCs) maintain nuclear permeability and nucleocytoplasmic transport via nucleoporins (Nups).
  • NPCs are disrupted in aged cells, but their role in aging is unclear.
  • The replicative life span (RLS) of Saccharomyces cerevisiae serves as a model for aging studies.

Purpose of the Study:

  • To investigate the role of specific nucleoporins and transport events in regulating longevity.
  • To determine if NPC function influences aging independently of permeability changes.
  • To explore the connection between NPC components, nucleocytoplasmic transport, and mitochondrial function in aging.

Main Methods:

  • Utilized Saccharomyces cerevisiae replicative life span (RLS) assays.
  • Generated and analyzed mutants lacking specific nucleoporin domains (e.g., Nup116 GLFG domain) and null mutants (e.g., nup100-null).
  • Assessed nuclear import of karyopherin Kap121 and mitochondrial function.
  • Quantified Nup116 levels and Kap121-dependent transport in aged yeast.
  • Overexpressed GSP1 (small GTPase) to evaluate rescue effects.

Main Results:

  • Mutants lacking the Nup116 GLFG domain showed decreased RLS, while nup100-null mutants exhibited increased longevity.
  • Nup116 mediates nuclear import of Kap121, crucial for mitochondrial function.
  • Kap121-dependent transport and Nup116 levels decline in aged yeast.
  • GSP1 overexpression rescued mitochondrial and RLS defects in nup116 mutants and extended RLS in wild-type cells.

Conclusions:

  • Specific nucleoporins and nucleocytoplasmic transport events directly influence cellular aging and longevity.
  • NPC-mediated transport, particularly of Kap121 by Nup116, is critical for maintaining mitochondrial function and lifespan.
  • Targeting NPC transport pathways may offer novel strategies for modulating aging.