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Title: Novel role of 4-hydroxy-2-nonenal in AIFm2-mediated mitochondrial stress signaling
Authors: 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
University of Kentucky
Louisiana State University in Shreveport
Mahidol University
University of Wisconsin Madison
Duke University Medical Center
University of Kentucky HealthCare
Keywords: Biochemistry, Genetics and Molecular Biology
Issue Date: 1-Feb-2016
Citation: Free Radical Biology and Medicine. Vol.91, (2016), 68-80
Abstract: © 2015 Elsevier Inc. All rights reserved. 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.
ISSN: 18734596
Appears in Collections:Scopus 2016-2017

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