Marion Schmidt

Publications (34) View all

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  Available from: Marion Schmidt

  Article: Aging: one thing leads to another.

  Marion Schmidt, Brian K Kennedy
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  ABSTRACT: Mitochondria deteriorate during the aging process, but the underlying mechanisms for the decline of this critical organelle are unknown. A new study indicates that in yeast an age-dependent reduction in vacuolar acidification leads to mitochondrial dysfunction through a surprising mechanism: loss of vacuolar neutral amino acid transport.
  Current biology: CB 12/2012; 22(24):R1048-51. · 10.99 Impact Factor
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  Available from: Marion Schmidt

  Article: The proteasome activator PA200 regulates tumor cell responsiveness to glutamine and resistance to ionizing radiation.

  Jennifer Blickwedehl, Scott Olejniczak, Ryan Cummings, Nilofar Sarvaiya, Ana Mantilla, Asher Chanan-Khan, Tej K Pandita, Marion Schmidt, Craig B Thompson, Naveen Bangia
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  ABSTRACT: The cellular response to ionizing radiation (IR) involves a variety of mechanisms to repair damage and maintain cell survival. We previously reported that the proteasome activator PA200 promotes long-term cell survival after IR exposure. The molecular function of PA200 is to enhance proteasome-mediated cleavage after glutamate; however, it is not known how this molecular function promotes survival after IR exposure. Here, we report that upon IR exposure, cellular demand for exogenous glutamine is increased. Cells containing PA200 are capable of surviving this IR-induced glutamine demand, whereas PA200-deficient cells show impaired long-term survival. Additional glutamine supplementation reverses the radiosensitivity of PA200-knockdown cells suggesting impaired glutamine homeostasis in these cells. Indeed, PA200-knockdown cells are unable to maintain intracellular glutamine levels. Furthermore, when extracellular glutamine is limiting, cells that contain PA200 respond by slowing growth, but PA200-knockdown cells and cells in which post-glutamyl proteasome activity is inhibited are nonresponsive and continue rapid growth. This cellular unresponsiveness to nutrient depletion is also reflected at the level of the mTOR substrate ribosomal S6 kinase (S6K). Thus, inability to restrict growth causes PA200-deficient cells to continue growing and eventually die due to lack of available glutamine. Together, these data indicate an important role for PA200 and post-glutamyl proteasome activity in maintaining glutamine homeostasis, which appears to be especially important for long-term survival of tumor cells after radiation exposure.
  Molecular Cancer Research 05/2012; 10(7):937-44. · 4.29 Impact Factor
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  Available from: Marion Schmidt

  Article: The yeast magmas ortholog pam16 has an essential function in fermentative growth that involves sphingolipid metabolism.

  Mary K Short, Joshua P Hallett, Krisztina Tar, Thomas Dange, Marion Schmidt, Robyn Moir, Ian M Willis, Paul T Jubinsky
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  ABSTRACT: Magmas is a growth factor responsive gene encoding an essential mitochondrial protein in mammalian cells. Pam16, the Magmas ortholog in Saccharomyces cerevisiae, is a component of the presequence translocase-associated motor. A temperature-sensitive allele (pam16-I61N) was used to query an array of non-essential gene-deletion strains for synthetic genetic interactions. The pam16-I61N mutation at ambient temperature caused synthetic lethal or sick phenotypes with genes involved in lipid metabolism, perixosome synthesis, histone deacetylation and mitochondrial protein import. The gene deletion array was also screened for suppressors of the pam16-I61N growth defect to identify compensatory pathways. Five suppressor genes were identified (SUR4, ISC1, IPT1, SKN1, and FEN1) and all are involved in sphingolipid metabolism. pam16-I61N cells cultured in glucose at non-permissive temperatures resulted in rapid growth inhibition and G1 cell cycle arrest, but cell viability was maintained. Altered mitochondria morphology, reduced peroxisome induction in glycerol/ethanol and oleate, and changes in the levels of several sphingolipids including C18 alpha-hydroxy-phytoceramide, were also observed in the temperature sensitive strain. Deletion of SUR4, the strongest suppressor, reversed the temperature sensitive fermentative growth defect, the morphological changes and the elevated levels of C18 alpha-hydroxy phytoceramide in pam16-I61N. Deletion of the other four suppressor genes had similar effects on C18 alpha-hydroxy-phytoceramide levels and restored proliferation to the pam16-I61N strain. In addition, pam16-I61N inhibited respiratory growth, likely by reducing cardiolipin, which is essential for mitochondrial function. Our results suggest that the pleiotropic effects caused by impaired Pam16/Magmas function are mediated in part by changes in lipid metabolism.
  PLoS ONE 01/2012; 7(7):e39428. · 4.09 Impact Factor
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  Available from: David Smith

  Article: Blm10 protein promotes proteasomal substrate turnover by an active gating mechanism.

  Thomas Dange, David Smith, Tahel Noy, Philipp C Rommel, Lukas Jurzitza, Radames J B Cordero, Anne Legendre, Daniel Finley, Alfred L Goldberg, Marion Schmidt
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  ABSTRACT: For optimal proteolytic function, the central core of the proteasome (core particle (CP) or 20S) has to associate with activators. We investigated the impact of the yeast activator Blm10 on proteasomal peptide and protein degradation. We found enhanced degradation of peptide substrates in the presence of Blm10 and demonstrated that Blm10 has the capacity to accelerate proteasomal turnover of the unstructured protein tau-441 in vitro. Mechanistically, proteasome activation requires the opening of a closed gate, which allows passage of unfolded proteins into the catalytic chamber. Our data indicate that gate opening by Blm10 is achieved via engagement of its C-terminal segment with the CP. Crucial for this activity is a conserved C-terminal YYX motif, with the penultimate tyrosine playing a preeminent role. Thus, Blm10 utilizes a gate opening strategy analogous to the proteasomal ATPases HbYX-dependent mechanism. Because gating incompetent Blm10 C-terminal point mutants confers a loss of function phenotype, we propose that the cellular function of Blm10 is based on CP association and activation to promote the degradation of proteasome substrates.
  Journal of Biological Chemistry 12/2011; 286(50):42830-9. · 4.77 Impact Factor
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  Available from: Krisztina Tar

  Article: Elevated proteasome capacity extends replicative lifespan in Saccharomyces cerevisiae.

  Undine Kruegel, Brett Robison, Thomas Dange, Günther Kahlert, Joe R Delaney, Soumya Kotireddy, Mitsuhiro Tsuchiya, Scott Tsuchiyama, Christopher J Murakami, Jennifer Schleit, George Sutphin, Daniel Carr, Krisztina Tar, Gunnar Dittmar, Matt Kaeberlein, Brian K Kennedy, Marion Schmidt
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  ABSTRACT: Aging is characterized by the accumulation of damaged cellular macromolecules caused by declining repair and elimination pathways. An integral component employed by cells to counter toxic protein aggregates is the conserved ubiquitin/proteasome system (UPS). Previous studies have described an age-dependent decline of proteasomal function and increased longevity correlates with sustained proteasome capacity in centenarians and in naked mole rats, a long-lived rodent. Proof for a direct impact of enhanced proteasome function on longevity, however, is still lacking. To determine the importance of proteasome function in yeast aging, we established a method to modulate UPS capacity by manipulating levels of the UPS-related transcription factor Rpn4. While cells lacking RPN4 exhibit a decreased non-adaptable proteasome pool, loss of UBR2, an ubiquitin ligase that regulates Rpn4 turnover, results in elevated Rpn4 levels, which upregulates UPS components. Increased UPS capacity significantly enhances replicative lifespan (RLS) and resistance to proteotoxic stress, while reduced UPS capacity has opposing consequences. Despite tight transcriptional co-regulation of the UPS and oxidative detoxification systems, the impact of proteasome capacity on lifespan is independent of the latter, since elimination of Yap1, a key regulator of the oxidative stress response, does not affect lifespan extension of cells with higher proteasome capacity. Moreover, since elevated proteasome capacity results in improved clearance of toxic huntingtin fragments in a yeast model for neurodegenerative diseases, we speculate that the observed lifespan extension originates from prolonged elimination of damaged proteins in old mother cells. Epistasis analyses indicate that proteasome-mediated modulation of lifespan is at least partially distinct from dietary restriction, Tor1, and Sir2. These findings demonstrate that UPS capacity determines yeast RLS by a mechanism that is distinct from known longevity pathways and raise the possibility that interventions to promote enhanced proteasome function will have beneficial effects on longevity and age-related disease in humans.
  PLoS Genetics 09/2011; 7(9):e1002253. · 8.69 Impact Factor