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Integrated Stress Response Potentiates Ponatinib-Induced Cardiotoxicity.

Gege Yan1, Zhenbo Han1, Youjeong Kwon1

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PubMed
Summary
This summary is machine-generated.

Ponatinib causes heart damage by disrupting mitochondrial energy production, activating the integrated stress response (ISR) via GCN2. Inhibiting the ISR protects against this cardiotoxicity, offering a potential therapeutic strategy.

Keywords:
GCN2ISRcardiotoxicitymitochondriaponatinib

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Area of Science:

  • Cardiology
  • Molecular Biology
  • Biochemistry

Background:

  • Mitochondrial dysfunction is a key factor in heart failure.
  • The interplay between mitochondrial energy production and signaling pathways is not fully understood.
  • Ponatinib, a leukemia drug, is known to cause cardiotoxicity through mitochondrial dysfunction.

Purpose of the Study:

  • To investigate the role of the integrated stress response (ISR) in ponatinib-induced cardiotoxicity.
  • To elucidate the molecular mechanisms linking mitochondrial stress to ISR activation by ponatinib.

Main Methods:

  • Utilized human induced pluripotent stem cell-derived cardiomyocytes and a mouse model.
  • Performed proteomic analysis, molecular, and biochemical assays.
  • Investigated the impact of ISR inhibition and NAD+ precursor supplementation.

Main Results:

  • Ponatinib activated the ISR in cardiac cells, with GCN2 identified as the key kinase.
  • Ponatinib inhibited ATP synthase, leading to ATP deficits that triggered ISR activation.
  • Decreased ATP levels facilitated direct activation of GCN2 by ponatinib.
  • ISR inhibition protected cardiomyocytes and attenuated cardiac dysfunction in mice without affecting ponatinib's anti-tumor effects.

Conclusions:

  • Neutralizing ISR hyperactivation can prevent or reverse ponatinib-induced cardiotoxicity.
  • Compromised ATP production potentiates GCN2-mediated ISR activation, with implications for various cardiac diseases.
  • Ponatinib directly activates GCN2, independent of its ATP-competitive kinase inhibition.