Key result
Aspartate supplementation reduced doxorubicin toxicity in S. cerevisiae by facilitating mitochondrial function, allowing cells to arrest growth and survive comparably to those in rich media.
Aspartate supplementation reduces doxorubicin toxicity in yeast by facilitating mitochondrial function, suggesting a shift from glycolysis to mitochondrial respiration following doxorubicin exposure.
Premature for clinical use with doxorubicin; leaves open translation of mitochondrial rescue to mammalian cardiomyocytes.
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.
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Dornfeld et al. (2015) studied Doxorubicin toxicity. Aspartate supplementation vs. Minimal media without aspartate was evaluated on Doxorubicin toxicity and cell survival. Aspartate supplementation reduced doxorubicin toxicity in S. cerevisiae by facilitating mitochondrial function, allowing cells to arrest growth and survive comparably to those in rich media.
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