缪阿片受体介导的溶酶体内铁释放会增加线粒体铁、活性氧和细胞死亡水平。

NeuroImmune pharmacology and therapeutics Pub Date : 2023-03-25 Epub Date: 2022-09-14 DOI:10.1515/nipt-2022-0013
Peter W Halcrow, Nirmal Kumar, Emily Hao, Nabab Khan, Olimpia Meucci, Jonathan D Geiger
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摘要

目的:包括吗啡和 DAMGO 在内的阿片类药物可激活μ-阿片受体 (MOR)、增加细胞内活性氧 (ROS) 水平并诱导细胞死亡。亚铁(Fe2+)通过类似芬顿的化学作用增加 ROS 水平,而内溶酶体是 "铁代谢的主调节器",含有可随时释放的 Fe2+ 储存。然而,阿片类药物诱导的内溶酶体铁稳态变化和下游信号事件的机制仍不清楚:我们使用 SH-SY5Y 神经母细胞瘤细胞、流式细胞术和共聚焦显微镜来测量 Fe2+、ROS 水平和细胞死亡:结果:吗啡和DAMGO可使内溶酶体脱酸,降低内溶酶体Fe2+水平,增加细胞膜和线粒体Fe2+和ROS水平,使线粒体膜电位去极化,并诱导细胞死亡;非选择性MOR拮抗剂纳洛酮和选择性MOR拮抗剂β-氟曲沙明(β-FNA)可阻断这些效应。内溶酶体-铁螯合剂去铁胺抑制了阿片激动剂诱导的细胞膜和线粒体中 Fe2+ 和 ROS 的增加。内溶酶体驻留双孔通道抑制剂 NED-19 和线粒体通透性转换孔抑制剂 TRO 阻止了阿片类药物诱导的内溶酶体 Fe2+ 外流和线粒体中随后的 Fe2+ 积累:阿片激动剂诱导的细胞膜和线粒体中Fe2+和ROS的增加以及细胞死亡似乎是内溶酶体脱酸和内溶酶体铁池中Fe2+外流的下游过程,足以影响其他细胞器。
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Mu opioid receptor-mediated release of endolysosome iron increases levels of mitochondrial iron, reactive oxygen species, and cell death.

Objectives: Opioids including morphine and DAMGO activate mu-opioid receptors (MOR), increase intracellular reactive oxygen species (ROS) levels, and induce cell death. Ferrous iron (Fe2+) through Fenton-like chemistry increases ROS levels and endolysosomes are "master regulators of iron metabolism" and contain readily-releasable Fe2+ stores. However, mechanisms underlying opioid-induced changes in endolysosome iron homeostasis and downstream-signaling events remain unclear.

Methods: We used SH-SY5Y neuroblastoma cells, flow cytometry, and confocal microscopy to measure Fe2+ and ROS levels and cell death.

Results: Morphine and DAMGO de-acidified endolysosomes, decreased endolysosome Fe2+ levels, increased cytosol and mitochondria Fe2+ and ROS levels, depolarized mitochondrial membrane potential, and induced cell death; effects blocked by the nonselective MOR antagonist naloxone and the selective MOR antagonist β-funaltrexamine (β-FNA). Deferoxamine, an endolysosome-iron chelator, inhibited opioid agonist-induced increases in cytosolic and mitochondrial Fe2+ and ROS. Opioid-induced efflux of endolysosome Fe2+ and subsequent Fe2+ accumulation in mitochondria were blocked by the endolysosome-resident two-pore channel inhibitor NED-19 and the mitochondrial permeability transition pore inhibitor TRO.

Conclusions: Opioid agonist-induced increases in cytosolic and mitochondrial Fe2+ and ROS as well as cell death appear downstream of endolysosome de-acidification and Fe2+ efflux from the endolysosome iron pool that is sufficient to affect other organelles.

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