Autophagy is linked to cell death, yet the associated mechanisms are largely undercharacterized. We discovered that melanoma, which is generally resistant to drug-induced apoptosis, can undergo autophagic cell death with the participation of orphan nuclear receptor TR3. A sequence of molecular events leading to cellular demise is launched by a specific chemical compound, 1-(3,4,5-trihydroxyphenyl)nonan-1-one, newly acquired from screening a library of TR3-targeting compounds. The autophagic cascade comprises TR3 translocation to mitochondria through interaction with the mitochondrial outer membrane protein Nix, crossing into the mitochondrial inner membrane through Tom40 and Tom70 channel proteins, dissipation of mitochondrial membrane potential by the permeability transition pore complex ANT1–VDAC1 and induction of autophagy. This process leads to excessive mitochondria clearance and irreversible cell death. It implicates a new approach to melanoma therapy through activation of a mitochondrial signaling pathway that integrates a nuclear receptor with autophagy for cell death.

自噬与细胞死亡有关，但相关机制在很大程度上被低估了。我们发现，通常对药物诱导的细胞凋亡具有抵抗力的黑色素瘤可以在孤儿核受体 TR3 的参与下发生自噬性细胞死亡。导致细胞死亡的一系列分子事件由一种特定的化合物 1-(3,4,5-trihydroxyphenyl)nonan-1-one 启动，该化合物是从筛选 TR3 靶向化合物库中新获得的。自噬级联包括通过与线粒体外膜蛋白 Nix 相互作用的 TR3 易位到线粒体，通过 Tom40 和 Tom70 通道蛋白进入线粒体内膜，通过通透性转换孔复合物 ANT1-VDAC1 耗散线粒体膜电位和诱导自噬。这个过程导致过度的线粒体清除和不可逆的细胞死亡。它暗示了一种通过激活线粒体信号通路来治疗黑色素瘤的新方法，该通路将核受体与细胞死亡的自噬相结合。