Chang Sarah M, Bin Munim Muhammad, Trojan Sonia E, Shevzov-Zebrun Anna, Abbott Keene L, Vander Heiden Matthew G
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.
bioRxiv. 2025 May 10:2025.05.09.653205. doi: 10.1101/2025.05.09.653205.
The cell NAD+/NADH ratio can constrain biomass synthesis and influence proliferation in nutrient-limited environments. However, which cell processes regulate the NAD+/NADH ratio is not known. Here, we find that some cancer cells elevate the NAD+/NADH ratio in response to serine deprivation by increasing mitochondrial respiration. Cancer cells that elevate mitochondrial respiration have higher serine production and proliferation in serine limiting conditions than cells with no mitochondrial respiration response, independent of serine synthesis enzyme expression. Increases in mitochondrial respiration and the NAD+/NADH ratio promote serine synthesis regardless of whether serine is environmentally limiting. Lipid deprivation can also increase the NAD+/NADH ratio via mitochondrial respiration in some cells, including cells that do not increase respiration following serine deprivation. Thus, in cancer cells where lipid depletion raises the NAD+/NADH ratio, proliferation in serine depleted environments improves when lipids are also depleted. Taken together, these data suggest that changes in mitochondrial respiration in response to nutrient deprivation can influence the NAD+/NADH ratio in a cell-specific manner to impact oxidative biomass synthesis and proliferation. Given the complexity of tumor microenvironments, this work provides a metabolic framework for understanding how levels of more than one environmental nutrient affects cancer cell proliferation.
细胞的NAD⁺/NADH比值可限制生物量合成，并在营养受限环境中影响细胞增殖。然而，尚不清楚哪些细胞过程调节NAD⁺/NADH比值。在此，我们发现一些癌细胞通过增加线粒体呼吸来响应丝氨酸剥夺，从而提高NAD⁺/NADH比值。与无线粒体呼吸反应的细胞相比，线粒体呼吸增强的癌细胞在丝氨酸限制条件下具有更高的丝氨酸产生量和增殖能力，这与丝氨酸合成酶的表达无关。无论丝氨酸在环境中是否受限，线粒体呼吸的增加和NAD⁺/NADH比值的升高均能促进丝氨酸合成。在一些细胞中，包括在丝氨酸剥夺后不增加呼吸的细胞，脂质剥夺也可通过线粒体呼吸增加NAD⁺/NADH比值。因此，在脂质耗竭会提高NAD⁺/NADH比值的癌细胞中，当脂质也被耗尽时，其在丝氨酸耗尽环境中的增殖能力会得到改善。综上所述，这些数据表明，响应营养剥夺的线粒体呼吸变化可以以细胞特异性方式影响细胞内的NAD⁺/NADH比值，从而影响氧化生物量合成和细胞增殖。鉴于肿瘤微环境的复杂性，这项工作为理解多种环境营养物质水平如何影响癌细胞增殖提供了一个代谢框架。
