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Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
p53 prevents doxorubicin cardiotoxicity independently of its prototypical tumor suppressor activities
Jie Li1, Ping-Yuan Wang1, Nathaniel A Long1
1Cardiovascular Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892.
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 (p53 ) 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.
Insights
The tumor suppressor p53 protects against doxorubicin-induced cardiotoxicity by maintaining mitochondrial DNA (mtDNA) homeostasis. Loss of p53 function leads to cardiac dysfunction and mtDNA depletion, highlighting p53
Area of Science:
- Cardiology
- Oncology
- Genetics
Background:
- Doxorubicin is a chemotherapy drug known to cause cardiotoxicity.
- The genetic factors influencing susceptibility to doxorubicin-induced cardiotoxicity are not well understood.
- The tumor suppressor protein p53 plays a role in cellular stress responses.
Purpose of the Study:
- To investigate the role of p53 in doxorubicin-induced cardiotoxicity.
- To explore the mechanisms by which p53 influences cardiac function after doxorubicin treatment.
- To assess the potential of p53 and mitochondrial markers as prognostic indicators for cardiotoxicity.
Main Methods:
- Used a mouse model with varying p53 statuses (wild-type, p53-deficient, p53 R172H mutant).
- Administered doxorubicin in divided low doses to mimic clinical settings.
- Assessed left ventricular (LV) systolic function, cardiac oxidative metabolism, mitochondrial mass, and mitochondrial DNA (mtDNA) levels.
- Investigated the transactivation of TFAM and p53R2 by different p53 forms.
- Evaluated the effect of NAD+ precursor supplementation on cardiac function and mtDNA.
Main Results:
- p53-deficient mice showed significant left ventricular systolic dysfunction after doxorubicin treatment.
- This dysfunction was linked to reduced cardiac oxidative metabolism, mitochondrial mass, and mtDNA homeostasis.
- Mice with a p53 R172H mutation (retaining mitochondrial biogenesis capacity) were protected from doxorubicin-induced cardiac dysfunction and mtDNA loss.
- Wild-type and mutant p53 exhibited distinct mechanisms for transactivating TFAM and p53R2, crucial for mtDNA maintenance.
- NAD+ precursor supplementation prevented doxorubicin-induced mtDNA depletion and cardiac dysfunction.
Conclusions:
- The tumor suppressor activity of p53 is critical for preventing doxorubicin-induced cardiotoxicity, primarily through maintaining mtDNA homeostasis.
- Loss of p53 function leads to mtDNA depletion and cardiac dysfunction, suggesting mtDNA loss as a key mechanism in doxorubicin cardiomyopathy.
- p53's role in protecting mtDNA in human cardiomyocytes indicates potential prognostic utility of mitochondrial markers for cardiotoxicity.
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