TP53 codon 72 polymorphism affects accumulation of mtDNA damage in human cells

Human TP53 gene is characterised by a polymorphism at codon 72 leading to an Arginine‐to‐Proline (R/P)substitution. The two resulting p53 isoforms have a different subcellular localisation after stress (more nuclear or moremitochondrial for the P or R isoform, respectively). p53P72 variant is more efficient than p53R72 in inducing the expressionof genes involved in nuclear DNA repair. Since p53 is involved also in mitochondrial DNA (mtDNA) maintenance, wewondered whether these p53 isoforms are associated with different accumulation of mtDNA damage. We observed thatcells bearing p53R72 accumulate lower amount of mtDNA damage upon rotenone stress with respect to cells bearingp53P72, and that p53R72 co‐localises with polymerase gamma more than p53P72. We also analysed the in vivoaccumulation of heteroplasmy in a 300 bp fragment of mtDNA D‐loop of 425 aged subjects. We observed that subjects withheteroplasmy higher than 5% are significantly less than expected in the p53R72/R72 group. On the whole, these datasuggest that the polymorphism of TP53 at codon 72 affects the accumulation of mtDNA mutations, likely through thedifferent ability of the two p53 isoforms to bind to polymerase gamma, and may contribute to in vivo accumulation ofmtDNA mutations.