title: Melatonin promotes Bax sequestration to mitochondria reducing cell susceptibility to apoptosis via the lipoxygenase metabolite 5-hydroxyeicosatetraenoic acid.
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(-5)M melatonin, respectively; the anti-apoptotic effect of melatonin is achieved at 10(-5)M, but drops to 10(-9)M 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.
authors.affiliation: Dipartimento di Biologia, Universita' di Roma Tor Vergata, Italy; Laboratoire de Biologie Moléculaire et Cellulaire du Cancer (LBMCC), Fondation Recherche sur le Cancer et les Maladies du Sang, Hôpital Kirchberg Luxembourg, Luxembourg.
authors.forename: F
authors.initials: F
authors.lastname: Radogna
authors.affiliation: Dipartimeno di Scienze Biomolecolari, Universita' di Urbino Carlo Bo, Italy.
authors.forename: M C
authors.initials: MC
authors.lastname: Albertini
authors.affiliation: Dipartimento di Biologia, Universita' di Roma Tor Vergata, Italy.
authors.forename: M
authors.initials: M
authors.lastname: De Nicola
authors.affiliation: Department of Pharmacy, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: M
authors.initials: M
authors.lastname: Diederich
authors.affiliation: Physical Science and Engineering Division, King Abdullah University of Science and Technology (KAUST), Saudi Arabia.
authors.forename: I
authors.initials: I
authors.lastname: Bejarano
authors.affiliation: Dipartimento di Biologia, Universita' di Roma Tor Vergata, Italy. Electronic address: ghibelli@uniroma2.it.
authors.forename: L
authors.initials: L
authors.lastname: Ghibelli
mesh_terms: D017209:Apoptosis; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism*; D002460:Cell Line; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism*; D008550:Melatonin / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism*; D009000:Monocytes / Q000187:drug effects / Q000502:physiology; D051028:bcl-2-Associated X Protein / Q000037:antagonists & inhibitors*
chemical_list: D006893:Hydroxyeicosatetraenoic Acids; D051028:bcl-2-Associated X Protein; C022022:5-hydroxy-6,8,11,14-eicosatetraenoic acid; D001094:Arachidonate 5-Lipoxygenase; C583212:ALOX5 protein, human; D008550:Melatonin
keywords: 5-HETE; Apoptosis; Bax; Bcl-2; IP3; Melatonin