Abstract
Cardiovascular complications are major side effects of many anticancer drugs. Accumulated evidence indicates that oxidative stress in mitochondria plays an important role in cardiac injury, but how mitochondrial redox mechanisms are involved in cardiac dysfunction remains unclear. Here, we demonstrate that 4-hydroxy-2-nonenal (HNE) activates the translocation of the mitochondrial apoptosis inducing factor (AIFm2) and facilitates apoptosis in heart tissue of mice and humans. Doxorubicin treatments significantly enhance cardiac levels of HNE and AIFm2. HNE adduction of AIFm2 inactivates the NADH oxidoreductase activity of AIFm2 and facilitates its translocation from mitochondria. His 174 on AIFm2 is the critical target of HNE adduction that triggers this functional switch. HNE adduction and translocation of AIFm2 from mitochondria upon Doxorubicin treatment are attenuated by superoxide dismutase mimetics. These results identify a previously unrecognized role of HNE with important consequences for mitochondrial stress signaling, heart failure, and the side effects of cancer therapy.
Original language | English |
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Pages (from-to) | 68-80 |
Number of pages | 13 |
Journal | Free Radical Biology and Medicine |
Volume | 91 |
DOIs | |
State | Published - Feb 2016 |
Bibliographical note
Publisher Copyright:© 2015 Elsevier Inc. All rights reserved.
Funding
This work is supported by NIH grants CA 139843 , CA 049797 , CA143428 , and the Edward P. Evans Foundation . The authors thank Dr. Carol Beach of the Free Radical Biology Core (FRBC) at the University of Kentucky for her help with the mass spectrometry analysis. This work is dedicated to the late Dr. Terry Oberley, for his critical contribution to the ultrastructural immunogold analysis, and for his leadership in the field of redox biology.
Funders | Funder number |
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National Institutes of Health (NIH) | CA143428, CA 049797 |
National Institutes of Health (NIH) | |
National Childhood Cancer Registry – National Cancer Institute | R01CA139843 |
National Childhood Cancer Registry – National Cancer Institute | |
Edward P Evans Foundation |
Keywords
- AIFm2
- HNE adduction
- Mitochondria
- Superoxide dismutase mimetics
ASJC Scopus subject areas
- Biochemistry
- Physiology (medical)