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Novel role of 4-hydroxy-2-nonenal in AIFm2-mediated mitochondrial stress signaling

Sumitra Miriyala1, Chadinee Thippakorn2, Luksana Chaiswing3

  • 1Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY, USA; Department of Cell Biology and Anatomy, Louisiana State University Health Sciences Center, Shreveport, LA, USA.

Free Radical Biology & Medicine
|December 23, 2015
PubMed

Insights

Oxidative stress from anticancer drugs causes heart damage. This study shows 4-hydroxy-2-nonenal (HNE) triggers mitochondrial AIFm2 release, leading to heart cell apoptosis and failure.

Area of Science:

  • Biochemistry
  • Cardiology
  • Molecular Biology

Background:

  • Cardiovascular complications are significant side effects of anticancer therapies.
  • Oxidative stress within mitochondria is implicated in cardiac injury, but specific mechanisms remain elusive.

Purpose of the Study:

  • To elucidate the role of mitochondrial redox mechanisms in chemotherapy-induced cardiac dysfunction.
  • To investigate the function of 4-hydroxy-2-nonenal (HNE) in mediating cardiac apoptosis.

Main Methods:

  • Investigated HNE adduction of mitochondrial apoptosis-inducing factor (AIFm2) in mouse and human heart tissues.
  • Analyzed the impact of doxorubicin treatment on cardiac HNE and AIFm2 levels.
  • Assessed the effect of superoxide dismutase mimetics on HNE-induced AIFm2 translocation.

Main Results:

  • Doxorubicin treatment increased cardiac HNE and AIFm2 levels.
  • HNE adducts inactivated AIFm2's NADH oxidoreductase activity, promoting its mitochondrial translocation.
  • Histidine 174 on AIFm2 was identified as the critical HNE target.
  • Superoxide dismutase mimetics reduced HNE adduction and AIFm2 translocation.

Conclusions:

  • Identified a novel role for HNE in activating AIFm2-mediated apoptosis in cardiac tissue.
  • This mechanism contributes to mitochondrial stress signaling, heart failure, and cancer therapy side effects.
  • Targeting HNE or AIFm2 may offer strategies to mitigate cardiotoxicity from anticancer drugs.
Keywords:
AIFm2HNE adductionMitochondriaSuperoxide dismutase mimetics

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