Cancer cells differentially modulate mitochondrial respiration to alter redox state and enable biomass synthesis in nutrient-limited environments

Cancer cells can modulate mitochondrial respiration to alter the redox state and support biomass synthesis in nutrient-depleted conditions, according to new research. The study reveals that the NAD+/NADH ratio, which governs biomass synthesis and proliferation, can be influenced by changes in mitochondrial respiration. Some cancer cells actively increase the NAD+/NADH ratio in response to serine deprivation by enhancing mitochondrial respiration.

This leads to higher serine production and cell proliferation, even when serine is limited in the environment. Interestingly, the increase in mitochondrial respiration and NAD+/NADH ratio promotes serine synthesis, irrespective of the availability of serine synthesis enzymes. Moreover, lipid deprivation can also raise the NAD+/NADH ratio through mitochondrial respiration in certain cancer cells, including those that do not increase respiration following serine deprivation.

Consequently, when both lipid and serine levels are depleted, proliferation improves in these cells. The research suggests that alterations in mitochondrial respiration triggered by nutrient deprivation can impact the NAD+/NADH ratio in a cell-specific manner, ultimately affecting oxidative biomass synthesis and proliferation. In conclusion, this work provides a metabolic framework for understanding how the availability of multiple environmental nutrients influences cancer cell proliferation within the complex tumor microenvironment.