Regulation of cancer cell metabolic adaptations via the UPRmt

癌细胞通常依赖糖酵解而不是呼吸，因为糖酵解的中间产物促进了细胞的快速增殖。然而，促进这种代谢适应的机制和条件尚不清楚。我们的实验室主要研究细胞如何在线粒体功能障碍期间调整转录以促进生存。利用线虫，实验室最近发现了转录因子ATFS-1，它通过线粒体蛋白输入效率来调节，在线粒体功能障碍或应激过程中诱导一些线粒体保护基因，称为线粒体未折叠蛋白反应(UPRmt)。这些转录本中包括线粒体伴侣蛋白、蛋白水解酶以及抗氧化机制。有趣的是，对这一提议至关重要的是，ATFS-1还诱导所有糖酵解成分，这表明当线粒体活性受损时，ATFS-1介导了ATP代谢向糖酵解的转变。据推测，通过UPRmt恢复能量不足的进化是为了在暴露于扰乱线粒体功能的条件下促进生存和线粒体修复。我们的实验室最近发现了ATF5，这是人类ATFS-1的同源基因，但它如何在高等真核生物中受到调控，以及它如何整合到癌细胞生理学中尚不清楚。我们的目标是利用线粒体功能完整的细胞系来加深我们对ATF5调控的理解，并确定ATF5在应对线粒体应激时调节哪些代谢途径。由于线粒体功能障碍在各种癌症中相对常见，我们的目标是进一步研究这些具有固有线粒体功能障碍或应激的癌细胞株的UPRmt调控，并确定ATF5如何协调呼吸和糖酵解来促进癌细胞存活。我们预计，对癌细胞如何适应代谢以应对线粒体功能障碍的更好理解可能会为未来的治疗提供建议。

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.