title: Aspartate facilitates mitochondrial function, growth arrest and survival during doxorubicin exposure.
abstract: Genomic screens of doxorubicin toxicity in S. cerevisiae have identified numerous mutants in amino acid and carbon metabolism which express increased doxorubicin sensitivity. This work examines the effect of amino acid metabolism on doxorubicin toxicity. S. cerevisiae were treated with doxorubicin in combination with a variety of amino acid supplements. Strains of S. cerevisiae with mutations in pathways utilizing aspartate and other metabolites were examined for sensitivity to doxorubicin. S. cerevisiae cultures exposed to doxorubicin in minimal media showed significantly more toxicity than cultures exposed in rich media. Supplementing minimal media with aspartate, glutamate or alanine reduced doxorubicin toxicity. Cell cycle response was assessed by examining the budding pattern of treated cells. Cultures exposed to doxorubicin in minimal media arrested growth with no apparent cell cycle progression. Aspartate supplementation allowed cultures exposed to doxorubicin in minimal media to arrest after one division with a budding pattern and survival comparable to cultures exposed in rich media. Aspartate provides less protection from doxorubicin in cells mutant in either mitochondrial citrate synthase (CIT1) or NADH oxidase (NDI1), suggesting aspartate reduces doxorubicin toxicity by facilitating mitochondrial function. These data suggest glycolysis becomes less active and mitochondrial respiration more active following doxorubicin exposure.
authors: a Department of Biomedical Sciences ; University of Minnesota Medical School, Duluth campus ; Duluth , MN USA.|b Department of Radiation Oncology ; Essentia Health ; Duluth , MN USA.
authors: Ken
authors: K
authors: Dornfeld
authors: a Department of Biomedical Sciences ; University of Minnesota Medical School, Duluth campus ; Duluth , MN USA.
authors: Michael
authors: M
authors: Madden
authors: a Department of Biomedical Sciences ; University of Minnesota Medical School, Duluth campus ; Duluth , MN USA.
authors: Andrew
authors: A
authors: Skildum
authors: a Department of Biomedical Sciences ; University of Minnesota Medical School, Duluth campus ; Duluth , MN USA.
authors: Kendall B
authors: KB
authors: Wallace
mesh_terms: D001224:Aspartic Acid / Q000378:metabolism* / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004317:Doxorubicin / Q000633:toxicity*; D006131:Growth Inhibitors / Q000378:metabolism* / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology*; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000378:metabolism
chemical_list: D006131:Growth Inhibitors; D001224:Aspartic Acid; D004317:Doxorubicin
keywords: Doxorubicin; anaplerosis; citrate synthase; electron transport; growth arrest; mitochondria; stress response