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

Sumitra Miriyala, Chadinee Thippakorn, Luksana Chaiswing, Yong Xu, Teresa Noel, Artak Tovmasyan, Ines Batinic-Haberle, Craig W. Vander Kooi, Wang Chi, Ahmed Abdel Latif, Manikandan Panchatcharam, Virapong Prachayasittikul, D. Allan Butterfield, Mary Vore, Jeffrey Moscow, Daret K.St Clair

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

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 languageEnglish
Pages (from-to)68-80
Number of pages13
JournalFree Radical Biology and Medicine
Volume91
DOIs
StatePublished - Feb 2016

Bibliographical note

Funding Information:
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.

Publisher Copyright:
© 2015 Elsevier Inc. All rights reserved.

Keywords

  • AIFm2
  • HNE adduction
  • Mitochondria
  • Superoxide dismutase mimetics

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

Fingerprint

Dive into the research topics of 'Novel role of 4-hydroxy-2-nonenal in AIFm2-mediated mitochondrial stress signaling'. Together they form a unique fingerprint.

Cite this