Novel role of 4-hydroxy-2-nonenal in AIFm2-mediated mitochondrial stress signaling
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.
AIFm2, HNE adduction, Mitochondria, Superoxide dismutase mimetics
Free Radical Biology and Medicine
Digital Object Identifier (DOI)
Miriyala, Sumitra; Thippakorn, Chadinee; Chaiswing, Luksana; Xu, Yong; Noel, Teresa; Tovmasyan, Artak; Batinic-Haberle, Ines; Vander Kooi, Craig W.; Chi, Wang; Latif, Ahmed Abdel; Panchatcharam, Manikandan; Prachayasittikul, Virapong; Allan Butterfield, D.; Vore, Mary; Moscow, Jeffrey; and Clair, Daret K.St, "Novel role of 4-hydroxy-2-nonenal in AIFm2-mediated mitochondrial stress signaling" (2016). Translational Neuroscience. 1282.