p53 prevents doxorubicin cardiotoxicity independently of its prototypical tumor suppressor activities

Proc Natl Acad Sci U S A. 2019 Sep 24;116(39):19626-19634. doi: 10.1073/pnas.1904979116. Epub 2019 Sep 5.

Abstract

Doxorubicin is a widely used chemotherapeutic agent that causes dose-dependent cardiotoxicity in a subset of treated patients, but the genetic determinants of this susceptibility are poorly understood. Here, we report that a noncanonical tumor suppressor activity of p53 prevents cardiac dysfunction in a mouse model induced by doxorubicin administered in divided low doses as in the clinics. While relatively preserved in wild-type (p53+/+ ) state, mice deficient in p53 (p53-/- ) developed left ventricular (LV) systolic dysfunction after doxorubicin treatment. This functional decline in p53-/- mice was associated with decreases in cardiac oxidative metabolism, mitochondrial mass, and mitochondrial genomic DNA (mtDNA) homeostasis. Notably, mice with homozygous knockin of the p53 R172H (p53172H/H ) mutation, which like p53-/- state lacks the prototypical tumor suppressor activities of p53 such as apoptosis but retains its mitochondrial biogenesis capacity, showed preservation of LV function and mitochondria after doxorubicin treatment. In contrast to p53-null state, wild-type and mutant p53 displayed distinct mechanisms of transactivating mitochondrial transcription factor A (TFAM) and p53-inducible ribonucleotide reductase 2 (p53R2), which are involved in mtDNA transcription and maintenance. Importantly, supplementing mice with a precursor of NAD+ prevented the mtDNA depletion and cardiac dysfunction. These findings suggest that loss of mtDNA contributes to cardiomyopathy pathogenesis induced by doxorubicin administered on a schedule simulating that in the clinics. Given a similar mtDNA protection role of p53 in doxorubicin-treated human induced pluripotent stem cell (iPSC)-derived cardiomyocytes, the mitochondrial markers associated with cardiomyopathy development observed in blood and skeletal muscle cells may have prognostic utility.

Keywords: anthracycline; cardiomyopathy; mitochondria; mtDNA; p53.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Apoptosis / physiology
  • Cardiomyopathies / metabolism
  • Cardiotoxicity / metabolism*
  • Cardiotoxicity / prevention & control*
  • DNA, Mitochondrial / genetics
  • DNA-Binding Proteins
  • Doxorubicin / toxicity*
  • Heart Diseases / metabolism
  • Humans
  • Induced Pluripotent Stem Cells / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitochondria, Heart / metabolism
  • Mitochondrial Proteins
  • Mutation
  • Myocytes, Cardiac / metabolism
  • Organelle Biogenesis
  • Primary Cell Culture
  • Transcription Factors
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*

Substances

  • DNA, Mitochondrial
  • DNA-Binding Proteins
  • Mitochondrial Proteins
  • TP53 protein, human
  • Transcription Factors
  • Trp53 protein, mouse
  • Tumor Suppressor Protein p53
  • mitochondrial transcription factor A
  • Doxorubicin