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dc.contributor.authorRadogna, Flavia
dc.contributor.authorAlbertini, M. C.
dc.contributor.authorDe Nicola, Milena D.
dc.contributor.authorDiederich, Marc
dc.contributor.authorBejarano, Ignacio
dc.contributor.authorGhibelli, Lina
dc.date.accessioned2015-08-03T12:31:52Z
dc.date.available2015-08-03T12:31:52Z
dc.date.issued2015-03
dc.identifier.citationRadogna, F., Albertini, M. C., De Nicola, M., Diederich, M., Bejarano, I., & Ghibelli, L. (2015). Melatonin promotes Bax sequestration to mitochondria reducing cell susceptibility to apoptosis via the lipoxygenase metabolite 5-hydroxyeicosatetraenoic acid. Mitochondrion, 21, 113–121. doi:10.1016/j.mito.2015.02.003
dc.identifier.issn15677249
dc.identifier.pmid25702644
dc.identifier.doi10.1016/j.mito.2015.02.003
dc.identifier.urihttp://hdl.handle.net/10754/564094
dc.description.abstractExtra-neurological functions of melatonin include control of the immune system and modulation of apoptosis. We previously showed that melatonin inhibits the intrinsic apoptotic pathway in leukocytes via stimulation of high affinity MT1/MT2 receptors, thereby promoting re-localization of the anti-apoptotic Bcl-2 protein to mitochondria. Here we show that Bcl-2 sequesters pro-apoptotic Bax into mitochondria in an inactive form after melatonin treatment, thus reducing cell propensity to apoptosis. Bax translocation and the anti-apoptotic effect of melatonin are strictly dependent on the presence of Bcl-2, and on the 5-lipoxygenase (5-LOX) metabolite 5-hydroxyeicosatetraenoic acid (5-HETE), which we have previously shown to be produced as a consequence of melatonin binding to its low affinity target calmodulin. Therefore, the anti-apoptotic effect of melatonin requires the simultaneous, independent interaction with high (MT1/MT2) and low (calmodulin) affinity targets, eliciting two independent signal transduction pathways converging into Bax sequestration and inactivation. MT1/MT2 vs. lipoxygenase pathways are activated by 10-9 vs. 10-5M melatonin, respectively; the anti-apoptotic effect of melatonin is achieved at 10-5M, but drops to 10-9M upon addition of exogenous 5-HETE, revealing that lipoxygenase activation is the rate-limiting pathway. Therefore, in areas of inflammation with increased 5-HETE levels, physiological nanomolar concentrations of melatonin may suffice to maintain leukocyte viability.
dc.publisherElsevier BV
dc.subject5-HETE
dc.subjectApoptosis
dc.subjectBax
dc.subjectBcl-2
dc.subjectIP3
dc.subjectMelatonin
dc.titleMelatonin promotes Bax sequestration to mitochondria reducing cell susceptibility to apoptosis via the lipoxygenase metabolite 5-hydroxyeicosatetraenoic acid
dc.typeArticle
dc.contributor.departmentMaterial Science and Engineering Program
dc.contributor.departmentPhysical Science and Engineering (PSE) Division
dc.identifier.journalMitochondrion
dc.contributor.institutionUniv Roma Tor Vergata, Dept Chem Sci & Technol, Rome, Italy
dc.contributor.institutionHop Kirchberg Luxembourg, Fdn Rech Canc & Malad Sang, LBMCC, Luxembourg, Luxembourg
dc.contributor.institutionUniv Urbino Carlo Bo, Ist Chim Biol, Rome, Italy
dc.contributor.institutionSeoul Natl Univ, Coll Pharm, Dept Pharm, Seoul 151, South Korea
kaust.personBejarano, Ignacio


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