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    Melatonin promotes Bax sequestration to mitochondria reducing cell susceptibility to apoptosis via the lipoxygenase metabolite 5-hydroxyeicosatetraenoic acid

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    Type
    Article
    Authors
    Radogna, Flavia
    Albertini, M. C.
    De Nicola, Milena D.
    Diederich, Marc
    Bejarano, Ignacio
    Ghibelli, Lina
    KAUST Department
    Material Science and Engineering Program
    Physical Science and Engineering (PSE) Division
    Date
    2015-03
    Permanent link to this record
    http://hdl.handle.net/10754/564094
    
    Metadata
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    Abstract
    Extra-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.
    Publisher
    Elsevier BV
    Journal
    Mitochondrion
    DOI
    10.1016/j.mito.2015.02.003
    PubMed ID
    25702644
    ae974a485f413a2113503eed53cd6c53
    10.1016/j.mito.2015.02.003
    Scopus Count
    Collections
    Articles; Physical Science and Engineering (PSE) Division; Material Science and Engineering Program

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