p53 prevents doxorubicin cardiotoxicity independently of its prototypical tumor suppressor activities

Significance Doxorubicin is a DNA-damaging agent that is highly effective against various types of cancers, but a subset of treated patients develop heart failure for unclear genetic reasons. In the current study using p53 mouse models, low-dose doxorubicin as administered in the clinics surprisingly revealed that the absence of p53 increases susceptibility to doxorubicin cardiotoxicity while a mutant of p53 that retains mitochondrial regulation is protective. Notably, promoting mitochondrial biogenesis with a simple vitamin supplement ameliorated the cardiotoxicity. Furthermore, mitochondrial blood markers observed in association with doxorubicin susceptibility could provide guidance for the safer use of this effective chemotherapy.