AIF promotes a JNK1-mediated cadherin switch independently of respiratory chain stabilization

Apoptosis-inducing factor (AIF) is a mitochondrial flavoprotein occasionally involved in cell death that primarily regulates mitochondrial energy metabolism under normal cellular conditions. AIF catalyzes the oxidation of NADH in vitro, yet the significance of this redox activity in cells remains un...

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Bibliographic Details
Published in:The Journal of biological chemistry 2018-09, Vol.293 (38), p.14707-14722
Main Authors: Scott, Andrew J., Walker, Sierra A., Krank, Joshua J., Wilkinson, Amanda S., Johnson, Kaitlyn M., Lewis, Eric M., Wilkinson, John C.
Format: Article
Language:English
Subjects:
Antigens, CD - metabolism
Apoptosis
Apoptosis Inducing Factor - physiology
Cadherins - metabolism
cancer
Catalysis
Cell Biology
Cell Line
cell signaling
Electron Transport
Energy Metabolism
Enzyme Activation
epithelial-mesenchymal transition (EMT)
Extracellular Signal-Regulated MAP Kinases - metabolism
Humans
MAPK
metabolism
mitochondria
Mitochondria - enzymology
Mitochondria - metabolism
Mitogen-Activated Protein Kinase 8 - metabolism
Oxidants - metabolism
Oxidation-Reduction
Oxidative Stress
p38 Mitogen-Activated Protein Kinases - metabolism
Phosphorylation
Signal Transduction
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Summary:Apoptosis-inducing factor (AIF) is a mitochondrial flavoprotein occasionally involved in cell death that primarily regulates mitochondrial energy metabolism under normal cellular conditions. AIF catalyzes the oxidation of NADH in vitro, yet the significance of this redox activity in cells remains unclear. Here, we show that through its enzymatic activity AIF is a critical factor for oxidative stress-induced activation of the mitogen-activated protein kinases JNK1 (c-Jun N-terminal kinase), p38, and ERK (extracellular signal-regulated kinase). AIF-dependent JNK1 signaling culminates in the cadherin switch, and genetic reversal of this switch leads to apoptosis when AIF is suppressed. Notably, this widespread ability of AIF to promote JNK signaling can be uncoupled from its more limited role in respiratory chain stabilization. Thus, AIF is a transmitter of extra-mitochondrial signaling cues with important implications for human development and disease.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.RA118.004022