LUNG TUMOR RESPIRATION DEFECTS LIMIT SERINE SYNTHESIS REQUIRED TO SUPPRESS OXIDATIVE STRESS

Mitochondrial function is important for both energetic and anabolic metabolism. Pathogenic mitochondrial DNA (mtDNA) mutations directly impact these functions, resulting in the detrimental consequences seen in human mitochondrial diseases. The role of pathogenic mtDNA mutations in human cancers is less clear; while the accumulation of pathogenic mtDNA mutations is observed in some cancer types, it is almost absent in others. We report here that a high mtDNA mutation burden in non-small-cell lung cancer (NSCLC) promoted the accumulation of defective mitochondria, decreased tumor cell proliferation and viability, and increased mouse lifespan. In NSCLC cells, pathogenic mtDNA mutations increased glycolysis and caused dependence on glucose as a carbon source. The glucose dependency sustained glucose carbons for mitochondrial energetics but at the cost of insufficient glucose carbons for de novo serine synthesis. Insufficient serine synthesis, in turn, impaired the downstream synthesis of nucleotides and glutathione, which was responsible for defective growth and survival. While NSCLCs are not sensitive to dietary deprivation of serine and glycine, NSCLCs with pathogenic mtDNA mutations were sensitive, resulting in further defects in tumor growth and lifespan extension. Thus, NSCLCs require mitochondrial function specifically to sustain sufficient serine synthesis for nucleotide production and redox homeostasis to support tumor growth. The essential dependence on glucose as a fuel source that results from defective mitochondria explains why these cancers preserve functional mtDNA, revealing that inhibiting mitochondrial function in conjunction with limiting dietary serine and glycine may be therapeutically exploitable.