Mutations to mitochondrial (mt) DNA occur with variable frequency in cancer but their effects are not clearly understood. Researchers co-led by Ludwig Princeton’s Eileen White reported in an August issue of Nature Communications their examination of the matter in mouse models of non-small cell lung cancer (NSCLC). The researchers introduced a proofreading mutant of DNA polymerase gamma (PolGD256A) into the KP model of NSCLC, which closely mimics the human version of the cancer, to generate PGKP mice. Eileen and her colleagues found that mutations to mtDNA in PGKP mouse tumors caused an accumulation of defective mitochondria in NSCLC cells, reduced the proliferation and viability of those cells and were associated with better survival of the mice. Mitochondrial dysfunction, they found, causes defective respiration in NSCLC cells, making their metabolism highly dependent on glucose. Those defects also cause an accumulation of the coenzyme NADH in the cells, which compromises the biosynthesis of the amino acid serine, the antioxidant glutathione and nucleotides. Dietary serine/glycine depletion further suppressed tumor growth in mice and that suppression could be reversed in cell culture with glutathione supplementation. The findings show that mitochondrial health is essential to maintaining adequate serine synthesis, which in turn supports the anabolic metabolism and redox homeostasis required for NSCLC tumor growth.
Respiration defects limit serine synthesis required for lung cancer growth and survival
Nature Communications, 2025 August 15