Effect of mitochondrial electron transport chain blockade on transcriptomic profile in human H460 cells

Cancer cells reprogram their metabolism to support cell growth and proliferation in harsh environments. To assess how human cells respond to defective mitochondrial respiration, we analyzed metabolomics profiles in cells with deficient electron transport chain (ETC). We found that ETC deficiency induces an accumulation of purine nucleotides. Additionally, we revealed that ETC blockade suppressed de novo purine nucleotide biosynthesis while enhanced purine salvage. This metabolic rewiring of purine nucleotide biosynthesis is not regulated at the transcriptional level. Instead, stable isotope tracing experiments showed that ETC blockade promoted the oxidative branch of pentose phosphate pathway to elevate phosphoribosyl diphosphate to drive purine salvage. In summary, our findings delineate how cells remodel purine metabolism in response to ETC blockade, and uncover a new metabolic vulnerability in tumors with low respiration.