Regulation of cancer cell metabolic adaptations via the UPRmt

• Applicant: Dr. Anna Schulz
• Subject Area: Cell Biology
• Term: from 2015 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 271003040

Cancer cells typically rely on glycolysis relative to respiration, as the glycolytic intermediates promote rapid cellular proliferation. However, the mechanisms and conditions that contribute to this metabolic adaptation are unclear. Our lab primarily examines how cells adapt transcription to promote survival during mitochondrial dysfunction. Using C. elegans, the lab recently identified the transcription factor ATFS-1, which is regulated via mitochondrial protein-import efficiency and during mitochondrial dysfunction or stress induces a number of mitochondria protective genes known as the mitochondrial unfolded protein response (UPRmt). Included in these transcripts are mitochondrial chaperones, proteases as well as anti-oxidant machinery. Interestingly, and of central importance to this proposal, ATFS-1 also induces all glycolytic components suggesting that ATFS-1 mediates a shift in ATP metabolism to glycolysis when mitochondrial activity is impaired. Presumably, recovering the energetic deficit via the UPRmt evolved to promote survival and mitochondrial repair upon exposure to conditions that perturb mitochondrial function. Our lab recently discovered ATF5, the human ortholog of ATFS-1, but how it is regulated in higher eukaryotes and how it integrates into cancer cell physiology is unclear. We aim to utilize cell lines with intact mitochondrial function to further our understanding of ATF5 regulation and to determine which metabolic pathways are regulated by ATF5 in response to mitochondrial stress. Because mitochondrial dysfunction is relatively common in a variety of cancers, we aim to further investigate UPRmt regulation in these cancer cell lines with inherent mitochondrial dysfunction or stress and to determine how ATF5 coordinates respiration and glycolysis to promote cancer cell survival. We anticipate that a better understanding of how cancer cells adapt metabolism in response to mitochondrial dysfunction may suggest future therapies.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Cole Haynes, Ph.D.