title: Melatonin antagonizes the intrinsic pathway of apoptosis via mitochondrial targeting of Bcl-2.
abstract: We have recently shown that melatonin antagonizes damage-induced apoptosis by interaction with the MT-1/MT-2 plasma membrane receptors. Here, we show that melatonin interferes with the intrinsic pathway of apoptosis at the mitochondrial level. In response to an apoptogenic stimulus, melatonin allows mitochondrial translocation of the pro-apoptotic protein Bax, but it impairs its activation/dimerization The downstream apoptotic events, i.e. cytochrome c release, caspase 9 and 3 activation and nuclear vesiculation are equally impaired, indicating that melatonin interferes with Bax activation within mitochondria. Interestingly, we found that melatonin induces a strong re-localization of Bcl-2, the main Bax antagonist to mitochondria, suggesting that Bax activation may in fact be antagonized by Bcl-2 at the mitochondrial level. Indeed, we inhibit the melatonin anti-apoptotic effect (i) by silencing Bcl-2 with small interfering RNAs, or with small-molecular inhibitors targeted at the BH3 binding pocket in Bcl-2 (i.e. the one interacting with Bax); and (ii) by inhibiting melatonin-induced Bcl-2 mitochondrial re-localization with the MT1/MT2 receptor antagonist luzindole. This evidence provides a mechanism that may explain how melatonin through interaction with the MT1/MT2 receptors, elicits a pathway that interferes with the Bcl-2 family, thus modulating the cell life/death balance.
authors.affiliation: Dipartimento di Biologia, Università di Roma Tor Vergata, Rome, Italy.
authors.forename: Flavia
authors.initials: F
authors.lastname: Radogna
authors.forename: Silvia
authors.initials: S
authors.lastname: Cristofanon
authors.forename: Laura
authors.initials: L
authors.lastname: Paternoster
authors.forename: Maria
authors.initials: M
authors.lastname: D'Alessio
authors.forename: Milena
authors.initials: M
authors.lastname: De Nicola
authors.forename: Claudia
authors.initials: C
authors.lastname: Cerella
authors.forename: Mario
authors.initials: M
authors.lastname: Dicato
authors.forename: Marc
authors.initials: M
authors.lastname: Diederich
authors.forename: Lina
authors.initials: L
authors.lastname: Ghibelli
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D045304:Cytochromes c / Q000378:metabolism; D006801:Humans; D008550:Melatonin / Q000494:pharmacology*; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects*; D011691:Puromycin / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000494:pharmacology; D044122:Receptor, Melatonin, MT1 / Q000037:antagonists & inhibitors; D044123:Receptor, Melatonin, MT2 / Q000037:antagonists & inhibitors; D014363:Tryptamines / Q000494:pharmacology; D020298:U937 Cells; D051028:bcl-2-Associated X Protein / Q000502:physiology
chemical_list: D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D044122:Receptor, Melatonin, MT1; D044123:Receptor, Melatonin, MT2; D014363:Tryptamines; D051028:bcl-2-Associated X Protein; C057154:luzindole; D011691:Puromycin; D045304:Cytochromes c; D008550:Melatonin