Poly(ADP-ribose) Polymerase (PARP)-1-independent Apoptosis-inducing Factor (AIF) Release and Cell Death Are Induced by Eleostearic Acid and Blocked by α-Tocopherol and MEK Inhibition

Poly(ADP-ribose)polymerase-1 (PARP-1) is thought to be required for apoptosis-inducing factor (AIF) release from mitochondria in caspase-independent apoptosis. The mechanism by which AIF is released through PARP-1 remains unclear. Here, we provide evidence that PARP-1-independent AIF release and cel...

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Bibliographic Details
Published in:The Journal of biological chemistry 2010-04, Vol.285 (17), p.13079-13091
Main Authors: Kondo, Kazunari, Obitsu, Saemi, Ohta, Sayaka, Matsunami, Katsuyoshi, Otsuka, Hideaki, Teshima, Reiko
Format: Article
Language:English
Subjects:
Active Transport, Cell Nucleus - drug effects
AIF
alpha-Tocopherol - pharmacology
Animals
Antioxidants - pharmacology
Apoptosis
Apoptosis - drug effects
Apoptosis Inducing Factor - genetics
Apoptosis Inducing Factor - metabolism
bcl-2-Associated X Protein - genetics
bcl-2-Associated X Protein - metabolism
Caspase 3 - genetics
Caspase 3 - metabolism
Cell Biology
Cell Nucleus - genetics
Cell Nucleus - metabolism
DNA/Damage
Eleostearic Acid
Enzyme Inhibitors - pharmacology
ERK
Humans
Linolenic Acids - pharmacology
Lipid/Fatty Acid
Lipids
MAP Kinase Kinase Kinases - antagonists & inhibitors
MAP Kinase Kinase Kinases - genetics
MAP Kinase Kinase Kinases - metabolism
Mice
Neurochemistry
Neurons - metabolism
PARP-1
PC12 Cells
Phosphorylation - drug effects
Poly (ADP-Ribose) Polymerase-1
Poly(ADP-ribose) Polymerases - genetics
Poly(ADP-ribose) Polymerases - metabolism
Rats
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Summary:Poly(ADP-ribose)polymerase-1 (PARP-1) is thought to be required for apoptosis-inducing factor (AIF) release from mitochondria in caspase-independent apoptosis. The mechanism by which AIF is released through PARP-1 remains unclear. Here, we provide evidence that PARP-1-independent AIF release and cell death are induced by a trienoic fatty acid, α-eleostearic acid (α-ESA). α-ESA induced the caspase-independent and AIF-initiated apoptotic death of neuronal cell lines, independently of PARP-1 activation. The cell death was inhibited by the MEK inhibitor U0126 and by knockdown of MEK using small interfering RNA. However, inhibitors for JNK, p38 inhibitors, calpain, phospholipase A2, and phosphatidylinositol 3-kinase, did not block cell death. AIF was translocated to the nucleus after the induction of apoptosis by α-ESA in differentiated PC12 cells without activating caspase-3 and PARP-1. The α-ESA-mediated cell death was not inhibited by PARP inhibitor 3,4-dihydro-5-[4-(1-piperidinyl)butoxyl]-1(2H)-isoquinoline and by knockdown of PARP-1 using small interfering RNA. Unlike N-methyl-N′-nitro-N-nitrosoguanidine treatment, histone-phosphorylated histone 2AX was not phosphorylated by α-ESA, which suggests no DNA damage. Overexpression of Bcl-2 did not inhibit the cell death. α-ESA caused a small quantity of superoxide production in the mitochondria, resulting in the reduction of mitochondrial membrane potential, both of which were blocked by a trace amount of α-tocopherol localized in the mitochondria. Our results demonstrate that α-ESA induces PARP-1-independent AIF release and cell death without activating Bax, cytochrome c, and caspase-3. MEK is also a key molecule, although the link between ERK, AIF release, and cell death remains unknown. Finding molecules that regulate AIF release may be an important therapeutic target for the treatment of neuronal injury.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M109.044206