Antimycin A-induced cell death depends on AIF translocation through NO production and PARP activation and is not involved in ROS generation, cytochrome c release and caspase-3 activation in HL-60 cells

Ogita, Masaki; Ogita, Akira; Usuki, Yoshinosuke; Fujita, Ken‐ichi; Tanaka, Toshio

doi:10.1038/ja.2009.2

Cited by 9 publications

(6 citation statements)

References 36 publications

(38 reference statements)

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“…A recent study has shown that antimycin A induces calpain activation. 48 However, to the best of our knowledge, oligomycin has not been demonstrated to activate calpain. Finally, the supernatants in all of the mitochondria exposed to electron transport inhibitors were assayed for PKA activity and, as expected, increased C subunit release (as revealed by Western blot analysis) parallels enhanced kinase activity (data not shown).…”

Section: ■ Results and Discussionmentioning

confidence: 99%

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Proteolytic Regulation of the Mitochondrial cAMP-Dependent Protein Kinase

Shell

Lawrence

2012

Biochemistry

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The mitochondrial cAMP-dependent protein kinase (PKA) is activatable in a cAMP-independent fashion. The regulatory (R) subunits of the PKA holoenzyme (R2C2), but not the catalytic (C) subunits, suffer proteolysis upon exposure of bovine heart mitochondria to digitonin, Ca2+, and a myriad of electron transport inhibitors. Selective loss of both the RI- and RII-type subunits was demonstrated via western blot analysis and activation of the C subunit was revealed by phosphorylation of a validated PKA peptide substrate. Selective proteolysis transpires in a calpain-dependent fashion as demonstrated by exposure of the R and C subunits of PKA to calpain and by attenuation of R and C subunit proteolysis in the presence of calpain inhibitor I. By contrast, exposure of mitochondria to cAMP fails to promote R subunit degradation, although it does result in enhanced C subunit catalytic activity. Treatment of mitochondria with electron transport chain inhibitors rotenone, antimycin A, sodium azide, and oligomycin, as well as an uncoupler of oxidative phosphorylation, also elicits enhanced C subunit activity. These results are consistent with the notion that signals, originating from cAMP-independent sources, elicit enhanced mitochondrial PKA activity.

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Section: ■ Results and Discussionmentioning

confidence: 99%

“…Release of C subunit in the antimycin A-treated sample is attenuated by ALLN, while release is not affected by ALLN in the oligomycin-treated sample (Figure ). A recent study has shown that antimycin A induces calpain activation . However, to the best of our knowledge, oligomycin has not been demonstrated to activate calpain.…”

Section: Resultsmentioning

confidence: 99%

Proteolytic Regulation of the Mitochondrial cAMP-Dependent Protein Kinase

Shell

Lawrence

2012

Biochemistry

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“…The vacuole-targeting fungicidal activity of PMB against C. albicans , A. niger , and Mucor mucedo is enhanced in the presence of ionophores like monensin and salinomycin (Ogita et al, 2009b). An organosulfur compound, zwiebelane A, isolated from onion bulbs, also enhances the vacuole-targeting fungicidal activity of PMB (Borjihan et al, 2010).…”

Section: Fungicidal Activities Of Other Compounds That Target Vacuolesmentioning

confidence: 99%

Enhancing Effects on Vacuole-Targeting Fungicidal Activity of Amphotericin B

Ogita¹,

Fujita²,

Tanaka³

2012

Front. Microbio.

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Invasive fungal infections are major threats for immunocompromised patients as well as for those undergoing cancer chemotherapy. Amphotericin B (AmB), a classical antifungal drug with a polyene macrolide structure, is widely used for the control of serious fungal infections. However, the clinical use of this antifungal drug is limited by its side effects and the emergence of drug-resistant strains. AmB lethality has been generally attributed to alterations in plasma membrane ion permeability due to its specific binding to plasma membrane ergosterol. Recent studies with Saccharomyces cerevisiae and Candida albicans reveal the vacuole disruptive action as another cause of AmB lethality on the basis of marked amplification of its activity in combination with allicin, an allyl-sulfur compound from garlic. The enhancing effect of allicin is dependent on the inhibition of ergosterol-trafficking from the plasma membrane to the vacuole membrane, which is considered to be a cellular response to protect against disintegration of the vacuole membrane. The polyol macrolide niphimycin (NM) also possesses vacuole-targeting fungicidal activity, which is greater than that of AmB and nystatin. The alkyl side chain attached to the macrolide ring of NM is considered to possess an allicin-like inhibitory effect on the intracellular trafficking of ergosterol. The vacuole-targeting fungicidal activity was additionally detected with a bactericidal cyclic peptide polymyxin B (PMB), and was markedly enhanced when administered together with allicin, monensin, or salinomycin. The synergistic fungicidal activities of AmB and allicin may have significant implications for the development of vacuole-targeting chemotherapy against fungal infections.

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“…Ogita et al . have recently reported that antimycin A, a potent complex III inhibitor, induces nuclear translocation of AIF in a caspase 3-independent manner to show cytotoxicity against HL-60 cells [ 33 ]. However, in the present case, nuclear translocation of AIF was not observed ( Figure 5 B).…”

Section: Discussionmentioning

confidence: 99%

Programmed Cell Death Induced by (−)-8,9-Dehydroneopeltolide in Human Promyelocytic Leukemia HL-60 Cells under Energy Stress Conditions

2014

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(+)-Neopeltolide is a marine macrolide natural product that exhibits potent antiproliferative activity against several human cancer cell lines. Previous study has established that this natural product primarily targets the complex III of the mitochondrial electron transport chain. However, the biochemical mode-of-actions of neopeltolide have not been investigated in detail. Here we report that (−)-8,9-dehydroneopeltolide (8,9-DNP), a more accessible synthetic analogue, shows potent cytotoxicity against human promyelocytic leukemia HL-60 cells preferentially under energy stress conditions. Nuclear morphology analysis, as well as DNA ladder assay, indicated that 8,9-DNP induced significant nuclear condensation/fragmentation and DNA fragmentation, and these events could be suppressed by preincubating the cells with a pan-caspase inhibitor, N-benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethylketone (zVAD). Immunoblot analysis demonstrated the release of cytochrome c from the mitochondria and the cleavage of full-length caspase-3 and poly(ADP-ribose) polymerase (PARP). These results indicated that 8,9-DNP induced caspase-dependent apoptotic programmed cell death under energy stress conditions. It was also found that 8,9-DNP induced non-apoptotic cell death in the presence/absence of zVAD under energy stress conditions. Immunoblot analysis showed the intracytosolic release of apoptosis-inducing factor (AIF), although it did not further translocate to the nucleus. It appears most likely that, in the presence of zVAD, 8,9-DNP triggered necrotic cell death as a result of severe intracellular ATP depletion.

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Antimycin A-induced cell death depends on AIF translocation through NO production and PARP activation and is not involved in ROS generation, cytochrome c release and caspase-3 activation in HL-60 cells

Cited by 9 publications

References 36 publications

Proteolytic Regulation of the Mitochondrial cAMP-Dependent Protein Kinase

Proteolytic Regulation of the Mitochondrial cAMP-Dependent Protein Kinase

Enhancing Effects on Vacuole-Targeting Fungicidal Activity of Amphotericin B

Programmed Cell Death Induced by (−)-8,9-Dehydroneopeltolide in Human Promyelocytic Leukemia HL-60 Cells under Energy Stress Conditions

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