Melatonin promotes Bax sequestration to mitochondria reducing cell susceptibility to apoptosis via the lipoxygenase metabolite 5-hydroxyeicosatetraenoic acid
Albertini, M. C.
De Nicola, Milena D.
KAUST DepartmentMaterial Science and Engineering Program
Physical Science and Engineering (PSE) Division
Permanent link to this recordhttp://hdl.handle.net/10754/564094
MetadataShow full item record
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.
- Melatonin antagonizes the intrinsic pathway of apoptosis via mitochondrial targeting of Bcl-2.
- Authors: Radogna F, Cristofanon S, Paternoster L, D'Alessio M, De Nicola M, Cerella C, Dicato M, Diederich M, Ghibelli L
- Issue date: 2008 Apr
- Lipoxygenase-mediated pro-radical effect of melatonin via stimulation of arachidonic acid metabolism.
- Authors: Radogna F, Sestili P, Martinelli C, Paolillo M, Paternoster L, Albertini MC, Accorsi A, Gualandi G, Ghibelli L
- Issue date: 2009 Jul 15
- 15-Hydroxyeicosatetraenoic acid (15-HETE) protects pulmonary artery smooth muscle cells against apoptosis via HSP90.
- Authors: Zhang L, Ma J, Li Y, Guo L, Ran Y, Liu S, Jiang C, Zhu D
- Issue date: 2010 Aug 14
- ROCK pathway participates in the processes that 15-hydroxyeicosatetraenoic acid (15-HETE) mediated the pulmonary vascular remodeling induced by hypoxia in rat.
- Authors: Ma J, Liang S, Wang Z, Zhang L, Jiang J, Zheng J, Yu L, Zheng X, Wang R, Zhu D
- Issue date: 2010 Jan
- ERK1/2 regulates two sequential steps promoting monocyte survival to peroxynitrite.
- Authors: Cerioni L, Cantoni O
- Issue date: 2007 Jan