癌细胞通过差异调节线粒体呼吸改变氧化还原状态，在营养受限环境中实现生物量合成
Cancer cells differentially modulate mitochondrial respiration to alter redox state and enable biomass synthesis in nutrient-limited environments
癌细胞在丝氨酸缺乏时可通过增强线粒体呼吸提高 NAD+/NADH 比值，从而促进丝氨酸合成与增殖。研究发现，能提升线粒体呼吸的癌细胞在丝氨酸受限条件下丝氨酸产量和增殖能力更高，且这一效应不依赖丝氨酸合成酶的表达水平。线粒体呼吸与 NAD+/NADH 比值的上升促进丝氨酸合成，与环境中丝氨酸是否受限无关。脂质缺乏也能通过线粒体呼吸提高部分细胞的 NAD+/NADH 比值，包括对丝氨酸缺乏无呼吸响应增强的细胞；在这类细胞中，同时去除脂质可改善丝氨酸缺乏环境下的增殖。
来源：eLife · doi.org
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 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 affect cancer cell proliferation.