title: Novel role of 4-hydroxy-2-nonenal in AIFm2-mediated mitochondrial stress signaling.
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.
authors.affiliation: 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.
authors.forename: Sumitra
authors.initials: S
authors.lastname: Miriyala
authors.affiliation: Faculty of Medical Technology, Mahidol University, Bangkok, Thailand.
authors.forename: Chadinee
authors.initials: C
authors.lastname: Thippakorn
authors.affiliation: Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY, USA; Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, WI, USA.
authors.forename: Luksana
authors.initials: L
authors.lastname: Chaiswing
authors.affiliation: Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY, USA.
authors.forename: Teresa
authors.initials: T
authors.lastname: Noel
authors.affiliation: Department of Radiation Oncology, Duke University Medical Center, Durham, NC, USA.
authors.forename: Artak
authors.initials: A
authors.lastname: Tovmasyan
authors.affiliation: Department of Radiation Oncology, Duke University Medical Center, Durham, NC, USA.
authors.forename: Ines
authors.initials: I
authors.lastname: Batinic-Haberle
authors.affiliation: Department of Biochemistry, University of Kentucky, Lexington, KY, USA.
authors.forename: Craig W
authors.initials: CW
authors.lastname: Vander Kooi
authors.affiliation: Biostatistics Core, Markey Cancer Center, University of Kentucky, Lexington, KY, USA.
authors.forename: Wang
authors.initials: W
authors.lastname: Chi
authors.affiliation: Division of Cardiovascular Medicine, University of Kentucky, Lexington, KY, USA.
authors.forename: Ahmed Abdel
authors.initials: AA
authors.lastname: Latif
authors.affiliation: Department of Cell Biology and Anatomy, Louisiana State University Health Sciences Center, Shreveport, LA, USA.
authors.forename: Manikandan
authors.initials: M
authors.lastname: Panchatcharam
authors.affiliation: Faculty of Medical Technology, Mahidol University, Bangkok, Thailand.
authors.forename: Virapong
authors.initials: V
authors.lastname: Prachayasittikul
authors.affiliation: Department of Chemistry and Membrane Sciences, University of Kentucky, Lexington, KY, USA.
authors.forename: D Allan
authors.initials: DA
authors.lastname: Butterfield
authors.affiliation: Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY, USA.
authors.forename: Mary
authors.initials: M
authors.lastname: Vore
authors.affiliation: Markey Cancer Center, University of Kentucky, Lexington, KY, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Moscow
authors.affiliation: Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY, USA. Electronic address: dstcl00@uky.edu.
authors.forename: Daret K
authors.initials: DK
authors.lastname: St Clair
mesh_terms: D000447:Aldehydes / Q000378:metabolism*; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D004317:Doxorubicin / Q000633:toxicity; D006331:Heart Diseases / Q000139:chemically induced; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010088:Oxidoreductases / Q000378:metabolism*; D021381:Protein Transport; D015398:Signal Transduction
chemical_list: D000447:Aldehydes; D000903:Antibiotics, Antineoplastic; D051017:Apoptosis Regulatory Proteins; D004317:Doxorubicin; C530020:ferroptosis suppressor protein 1, mouse; D010088:Oxidoreductases; C027576:4-hydroxy-2-nonenal
keywords: AIFm2; HNE adduction; Mitochondria; Superoxide dismutase mimetics