期刊
MITOCHONDRION
卷 21, 期 -, 页码 113-121出版社
ELSEVIER SCI LTD
DOI: 10.1016/j.mito.2015.02.003
关键词
Melatonin; Bax; Bcl-2; Apoptosis; 5-HETE; IP3
资金
- Recherche Cancer et Sang foundation
- Recherches Scientifiques Luxembourg association
- Een Haerz fir kriibskrank Kanner
- Recherches Scientifiques Luxembourg
- Televie-Luxembourg
- Action Lions Vaincre le Cancer
- National Research Foundation of Korea (NRF) grant for the Global Core Research Center (GCRC) - Korea Government, Ministry of Science, ICT & Future Planning (MSIP) [2011-0030001]
- AbbVie [C78204]
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. Box 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 antiapoptotic 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. (C) 2015 Elsevier B.V. and Mitochondria Research Society. All rights reserved.
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