2. Academic Validation
  3. Novel role of 4-hydroxy-2-nonenal in AIFm2-mediated mitochondrial stress signaling

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

  • Free Radic Biol Med. 2016 Feb;91:68-80. doi: 10.1016/j.freeradbiomed.2015.12.002.
Sumitra Miriyala 1,  Chadinee Thippakorn 2,  Luksana Chaiswing 3,  Yong Xu 4,  Teresa Noel 4,  Artak Tovmasyan 5,  Ines Batinic-Haberle 5,  Craig W Vander Kooi 6,  Wang Chi 7,  Ahmed Abdel Latif 8,  Manikandan Panchatcharam 9,  Virapong Prachayasittikul 2,  D Allan Butterfield 10,  Mary Vore 4,  Jeffrey Moscow 11,  Daret K St Clair 12
Affiliations

Affiliations

  • 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: [email protected].
PMID: 26689472 DOI: 10.1016/j.freeradbiomed.2015.12.002
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.

Keywords

AIFm2; HNE adduction; Mitochondria; Superoxide dismutase mimetics.

Figures