Inhibition of oxidative metabolism leads to p53 genetic inactivation and transformation in neural stem cells

http://www.pnas.org/content/112/4/1059.full

Stefano Bartesaghi, Vincenzo Graziano, Sara Galavotti et al.

Evasion of cell death is known to be one of the hallmarks of cancer. As we know, mitochondria are central organelles to the execution of cell death, and are observed to be perturbed in cancer. In this study, the authors perturb the mitochondria of neural progenitor stem cells in two ways. Firstly, through knockdown of NDUFA10 (a subunit of complex I), they find a shift to glycolytic metabolism and an increase in cell confluence (i.e. cell growth). They then interfere with the gene TK2, which is involved in mtDNA biosynthesis. Perhaps surprisingly, they find TK2 KO cells have a higher ATP yield that the wild-type, despite their glycolytic shift. These cells also had increased cell diameter, an accumulation of cells in S-phase and resistance to differentiation. They found that these KO cells did not tend to express the pro-apoptotic transcription factor p53, rather a shorter isoform Δp53, and were more susceptible to neoplastic transformation.