Sumitra Miriyala1, Chadinee Thippakorn2, Luksana Chaiswing3, Yong Xu4, Teresa Noel4, Artak Tovmasyan5, Ines Batinic-Haberle5, Craig W Vander Kooi6, Wang Chi7, Ahmed Abdel Latif8, Manikandan Panchatcharam9, Virapong Prachayasittikul2, D Allan Butterfield10, Mary Vore4, Jeffrey Moscow11, Daret K St Clair12. 1. Department 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. 2. Faculty of Medical Technology, Mahidol University, Bangkok, Thailand. 3. Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY, USA; Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, WI, USA. 4. Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY, USA. 5. Department of Radiation Oncology, Duke University Medical Center, Durham, NC, USA. 6. Department of Biochemistry, University of Kentucky, Lexington, KY, USA. 7. Biostatistics Core, Markey Cancer Center, University of Kentucky, Lexington, KY, USA. 8. Division of Cardiovascular Medicine, University of Kentucky, Lexington, KY, USA. 9. Department of Cell Biology and Anatomy, Louisiana State University Health Sciences Center, Shreveport, LA, USA. 10. Department of Chemistry and Membrane Sciences, University of Kentucky, Lexington, KY, USA. 11. Markey Cancer Center, University of Kentucky, Lexington, KY, USA. 12. Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY, USA. Electronic address: dstcl00@uky.edu.
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.
Cardiovascular complications are major side effects of many antin class="Disease">cancer 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 NADHoxidoreductase 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.
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