Morphine induces dysfunction of PINK1/Parkin-mediated mitophagy in spinal cord neurons implying involvement in antinociceptive tolerance
Morphine induces dysfunction of PINK1/Parkin-mediated mitophagy in spinal cord neurons implying involvement in antinociceptive tolerance
复制标题
吗啡诱导脊髓神经元中 PINK1/Parkin 介导的线粒体自噬功能障碍，这意味着参与抗伤害耐受
DOI：
10.1093/jmcb/mjz002
复制
发表时间：
2019-12-01
影响因子：
5.5
通讯作者：
Liu, Wen-Tao
中科院分区：
文献类型：
--
作者：
Kong, Hong;Jiang, Chun-Yi;Liu, Wen-Tao
阿片类药物诱导的镇痛耐受性的发展是长期使用治疗慢性疼痛的临床挑战。吗啡耐受的机制尚不清楚。线粒体源性活性氧（ROS）是诱导镇痛耐受和疼痛的重要信号。长期服用吗啡会导致活性氧的产生和受损线粒体的积累，这些线粒体会立即被线粒体自噬清除。在这里，我们发现吗啡抑制线粒体损伤诱导的pten诱导的推定激酶1 （PINK1）在神经元中的积累。它阻断Parkin向受损线粒体的募集，并抑制由Parkin催化的线粒体蛋白的泛素化。因此，吗啡抑制了LC3和sequestosome-1 （SQSTM1/p62）介导的自噬体对受损线粒体的识别。因此，吗啡抑制自噬通量，导致SQSTM1/p62的积累。最后，受损的线粒体不能被递送到溶酶体降解，最终诱导强大的ROS产生和吗啡耐受性。我们的研究结果表明，线粒体自噬功能障碍与吗啡耐受有关。PINK1/ parkin介导的受损线粒体清除缺失对于过量ROS的产生至关重要，对镇痛耐受性的发展也很重要。这些发现表明，能够稳定PINK1或恢复线粒体自噬的化合物可用于预防或减少慢性疼痛治疗期间的阿片类药物耐受性。
The development of opioid-induced analgesic tolerance is a clinical challenge in long-term use for managing chronic pain. The mechanisms of morphine tolerance are poorly understood. Mitochondria-derived reactive oxygen species (ROS) is a crucial signal inducing analgesic tolerance and pain. Chronic administration of morphine leads to robust ROS production and accumulation of damaged mitochondria, which are immediately removed by mitophagy. Here, we show that morphine inhibits mitochondria damage-induced accumulation of PTEN-induced putative kinase 1 (PINK1) in neurons. It interrupts the recruitment of Parkin to the impaired mitochondria and inhibits the ubiquitination of mitochondrial proteins catalyzed by Parkin. Consequently, morphine suppresses the recognition of autophagosomes to the damaged mitochondria mediated by LC3 and sequestosome-1 (SQSTM1/p62). Thus, morphine inhibits autophagy flux and leads to the accumulation of SQSTM1/p62. Finally, the impaired mitochondria cannot be delivered to lysosomes for degradation and ultimately induces robust ROS production and morphine tolerance. Our findings suggest that the dysfunction of mitophagy is involved in morphine tolerance. The deficiency of PINK1/Parkin-mediated clearance of damaged mitochondria is crucial for the generation of excessive ROS and important to the development of analgesic tolerance. These findings suggest that the compounds capable of stabilizing PINK1 or restoring mitophagy may be utilized to prevent or reduce opioid tolerance during chronic pain management.