Regulation of cancer cell metabolic adaptations via the UPRmt

癌细胞通常依赖于相对于呼吸的糖酵解，因为糖酵解中间体促进快速细胞增殖。然而，导致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适应转录，以促进线粒体功能障碍期间的生存。利用C.该实验室最近鉴定了转录因子ATFS-1，该转录因子通过线粒体蛋白质输入效率进行调节，并且在线粒体功能障碍或应激期间诱导许多线粒体保护基因，称为线粒体未折叠蛋白反应（UPRmt）。这些转录物中包括线粒体伴侣蛋白、蛋白酶以及抗氧化机制。有趣的是，并且对于该提议至关重要的是，ATFS-1还诱导所有糖酵解组分，这表明当线粒体活性受损时，ATFS-1介导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ATF 5，ATFS-1的人类直系同源物，但它如何在高等真核生物中调节以及如何整合到癌细胞生理学中尚不清楚。我们的目标是利用完整的线粒体功能的细胞系，以进一步了解ATF 5的调节，并确定哪些代谢途径是由ATF 5调节线粒体应激。由于线粒体功能障碍在各种癌症中相对常见，因此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压力的癌细胞系中的UPRmt调节，并确定ATF 5如何协调呼吸和糖酵解以促进癌细胞存活。我们预计，更好地了解癌细胞如何适应线粒体功能障碍的代谢可能会建议未来的治疗方法。

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.