title: Altering nuclear pore complex function impacts longevity and mitochondrial function in S. cerevisiae.
abstract: The eukaryotic nuclear permeability barrier and selective nucleocytoplasmic transport are maintained by nuclear pore complexes (NPCs), large structures composed of ∼ 30 proteins (nucleoporins [Nups]). NPC structure and function are disrupted in aged nondividing metazoan cells, although it is unclear whether these changes are a cause or consequence of aging. Using the replicative life span (RLS) of Saccharomyces cerevisiae as a model, we find that specific Nups and transport events regulate longevity independent of changes in NPC permeability. Mutants lacking the GLFG domain of Nup116 displayed decreased RLSs, whereas longevity was increased in nup100-null mutants. We show that Nup116 mediates nuclear import of the karyopherin Kap121, and each protein is required for mitochondrial function. Both Kap121-dependent transport and Nup116 levels decrease in replicatively aged yeast. Overexpression of GSP1, the small GTPase that powers karyopherin-mediated transport, rescued mitochondrial and RLS defects in nup116 mutants and increased longevity in wild-type cells. Together, these studies reveal that specific NPC nuclear transport events directly influence aging.
authors.affiliation: Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232.
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Lord
authors.affiliation: Laboratory of Cellular and Structural Biology, The Rockefeller University, New York, NY 10021.
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Timney
authors.affiliation: Laboratory of Cellular and Structural Biology, The Rockefeller University, New York, NY 10021.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Rout
authors.affiliation: Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232 susan.wente@vanderbilt.edu.
authors.forename: Susan R
authors.initials: SR
authors.lastname: Wente
mesh_terms: D021581:Active Transport, Cell Nucleus; D002467:Cell Nucleus / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000378:metabolism; D050296:Microbial Viability; D008928:Mitochondria / Q000502:physiology*; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism; D022022:Nuclear Pore / Q000502:physiology*; D028861:Nuclear Pore Complex Proteins / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D010539:Permeability; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000502:physiology*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism
chemical_list: C080324:GSP1 protein, S cerevisiae; D026901:Membrane Transport Proteins; C077730:NUP116 protein, S cerevisiae; D028861:Nuclear Pore Complex Proteins; D009687:Nuclear Proteins; C483822:PSE1 protein, S cerevisiae; D018160:Receptors, Cytoplasmic and Nuclear; D029701:Saccharomyces cerevisiae Proteins; D020559:Monomeric GTP-Binding Proteins