Mitochondrial Dysfunction Impairs Tumor Suppressor P53-Mediated Cell Death

To explore the tumor suppressing function of mitochondria we have investigated the link between mitochondrial dysfunction and the tumor suppressor protein p53. Using a set of respiration deficient (Res − ) cells with impaired respiratory chain (RC) assembly, we have determined the effects of mitochondrial dysfunction on p53‐mediated cell death. Our data show that normal mitochondrial function is required for γ‐irradiation induced cell death, which is mainly p53‐dependent. The Res − cells are protected against radiation induced death. Depending upon the type of RC deficiency, the p53 protein expression is differentially regulated. However, irrespective of the differences in p53 protein expression profile, the p53 transactivation activity is impaired in all Res − cells. As expected, the pharmacological inhibition of RC function also protects cells from radiation‐induced cell death. The negative effect of mitochondrial dysfunction on p53 expression/function is a reversible phenomenon. We believe that these findings provide a mechanistic basis for explaining the role of mitochondria as tumor suppressors, and also provide plausible link why age is the major risk factor for cancer considering mitochondrial function declines during ageing. Research support: Rays of Hope Foundation, startup funds, NIH grant to NY.