Poly (ADP‐ribose) polymerase 1‐mediated defective mitophagy contributes to painful diabetic neuropathy in the db/db model
Poly (ADP‐ribose) polymerase 1‐mediated defective mitophagy contributes to painful diabetic neuropathy in the db/db model
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聚（ADP-核糖）聚合酶 1 介导的线粒体自噬缺陷导致 db/db 模型中的疼痛性糖尿病神经病变
DOI：
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发表时间：
2022
影响因子：
4.7
通讯作者：
Zhongjie Liu
中科院分区：
文献类型：
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作者：
P. Yuan;Fuhu Song;Pian Zhu;K. Fan;Qinming Liao;Lijin Huang;Zhongjie Liu
研究表明，聚（ADP‐核糖）聚合酶1（PARP 1）参与糖尿病的病理过程。线粒体自噬被广泛认为是通过溶酶体降解受损线粒体来维持活性氧稳态的关键调节过程。然而，PARP 1在线粒体自噬相关的线粒体氧化损伤和疼痛性糖尿病神经病变（PDN）进展中的调节作用尚不清楚。在这项研究中，我们研究了在瘦素基因突变（db/db）PDN小鼠模型中PARP 1介导的线粒体自噬阻断的体外和体内机制。通过测定坐骨神经传导速度（SNCV）、机械性退缩阈值（MWT）和热性退缩潜伏期（TWL）建立Db/db小鼠PDN模型。结果表明，PDN小鼠背根神经节（DRG）神经元PARP 1活性增强，线粒体损伤明显，线粒体自噬功能受损。发现PARP 1介导从PDN小鼠分离的DRG神经元中的线粒体自噬损伤。PARP 1抑制剂（PJ 34或AG 14361）减轻糖尿病诱导的周围神经痛觉过敏，恢复背根神经节神经元线粒体吞噬功能并减少线粒体氧化损伤。溶酶体还原剂（DC 661）诱导的线粒体自噬损伤加重了糖尿病诱导的DRG神经元线粒体氧化应激和损伤。综上所述，我们的数据表明，PARP 1诱导的DRG神经元的线粒体自噬缺陷是糖尿病诱导的周围神经病理性损伤的关键机制。抑制PARP 1和恢复线粒体自噬功能是PDN的潜在治疗靶点。
Studies have shown that poly (ADP‐ribose) polymerase 1 (PARP1) is involved in the pathological process of diabetes. Mitophagy is widely acknowledged to be a key regulatory process in maintaining reactive oxygen species homeostasis via lysosome degradation of damaged mitochondria. However, the regulatory role of PARP1 in mitophagy‐related mitochondrial oxidative injury and progression of painful diabetic neuropathy (PDN) is unclear. In this study, we studied the in vitro and in vivo mechanisms of PARP1‐mediated mitophagy blockade in a leptin gene‐mutation (db/db) mouse model of PDN. Db/db mice models of PDN were established by assessing the sciatic nerve conduction velocity (SNCV), mechanical withdrawal threshold (MWT), and thermal withdrawal latency (TWL). The results showed that PARP1 activity and mitochondrial injury of dorsal root ganglion (DRG) neurons were increased, and mitophagy was impaired in PDN mice. PARP1 was found to mediate the impairment of mitophagy in DRG neurons isolated from PDN mice. PARP1 inhibitors (PJ34 or AG14361) attenuated diabetes‐induced peripheral nerve hyperalgesia, restored DRG neuron mitophagy function and decreased mitochondrial oxidative injury. Mitophagy impairment induced by lysosome deacidificant (DC661) aggravated diabetes‐induced DRG neuron mitochondrial oxidative stress and injury. Taken together, our data revealed that PARP1‐induced defective mitophagy of DRG neurons is a key mechanism in diabetes‐induced peripheral neuropathic injury. Inhibition of PARP1 and restoration of mitophagy function are potential therapeutic targets for PDN.
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