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

Document Type

Article

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

Publication Date

2-1-2016

Publication Title

Free Radical Biology and Medicine

ISSN

08915849

E-ISSN

18734596

Volume

91

First Page

68

Last Page

80

PubMed ID

26689472

Digital Object Identifier (DOI)

10.1016/j.freeradbiomed.2015.12.002

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