<br>SIRT3 通过介导 FoxO3a-PINK1-Parkin 信号通路激活线粒体自噬来减轻疼痛的糖尿病神经病变,CNS Neuroscience & Therapeutics

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SIRT3 通过介导 FoxO3a-PINK1-Parkin 信号通路激活线粒体自噬来减轻疼痛的糖尿病神经病变
CNS Neuroscience & Therapeutics ( IF 4.8 ) Pub Date : 2024-04-04 , DOI: 10.1111/cns.14703
Jing Yang ₁ , Zhuoying Yu ₁ , Ye Jiang ₁ , Zixian Zhang _{2,

3,

4} , Yue Tian _{2,

3,

4} , Jie Cai _{2,

3,

4} , Min Wei ₁ , Yanhan Lyu ₁ , Dongsheng Yang ₁ , Shixiong Shen ₁ , Guo-Gang Xing _{2,

3,

4} , Min Li ₁

Affiliation

简介疼痛性糖尿病神经病变（PDN）是糖尿病的常见并发症。既往研究表明线粒体功能障碍在PDN的发生中发挥一定作用，但其发病机制和机制尚未得到充分研究。方法本研究采用高脂饮食/低剂量链脲佐菌素诱导的大鼠作为模型。 2 糖尿病。行为测试、背根神经节 (DRG) 神经元的全细胞膜片钳记录和复杂的感觉神经传导速度研究用于评估周围神经病变。使用线粒体膜电位（MMP）、ATP、组织活性氧和透射电子显微镜来评估DRG中线粒体的功能和形态。通过实时PCR、蛋白质印迹和免疫荧光来研究其机制。结果我们发现PDN大鼠中受损的线粒体积累并且线粒体自噬受到抑制。 Sirtuin 3 (SIRT3) 的表达，它是一种 NAD +线粒体中依赖的脱乙酰酶被抑制。通过鞘内注射 LV-SIRT3 慢病毒，DRG 神经元中 SIRT3 过度表达可改善神经功能和线粒体功能障碍。异常性疼痛和伤害感受器过度兴奋性的逆转以及 MMP 和 ATP 水平的恢复证明了这一点。 SIRT3 的过表达通过激活 FoxO3a-PINK1-Parkin 信号通路来恢复受抑制的线粒体自噬。当鞘内注射 FoxO3a siRNA 时，SIRT3 过表达的影响（包括逆转异常性疼痛和伤害感受器过度兴奋性、改善受损的线粒体和线粒体自噬以及恢复 PINK1 和 Parkin 表达）被抵消。结论这些结果表明，SIRT3 过表达通过激活 FoxO3a-PINK1-Parkin 介导的线粒体自噬来改善 PDN，这表明 SIRT3 可能成为 PDN 的一种令人鼓舞的治疗策略。

"点击查看英文标题和摘要"

SIRT3 alleviates painful diabetic neuropathy by mediating the FoxO3a‐PINK1‐Parkin signaling pathway to activate mitophagy

IntroductionPainful diabetic neuropathy (PDN) is a common complication of diabetes. Previous studies have implicated that mitochondrial dysfunction plays a role in the development of PDN, but its pathogenesis and mechanism have not been fully investigated.MethodsIn this study, we used high‐fat diet/low‐dose streptozotocin‐induced rats as a model of type 2 diabetes mellitus. Behavioral testing, whole‐cell patch‐clamp recordings of dorsal root ganglion (DRG) neurons, and complex sensory nerve conduction velocity studies were used to assess peripheral neuropathy. Mitochondrial membrane potential (MMP), ATP, tissue reactive oxygen species, and transmission electron microscopy were used to evaluate the function and morphology of mitochondria in DRG. Real‐time PCR, western blot, and immunofluorescence were performed to investigate the mechanism.ResultsWe found that damaged mitochondria were accumulated and mitophagy was inhibited in PDN rats. The expression of sirtuin 3 (SIRT3), which is an NAD+‐dependent deacetylase in mitochondria, was inhibited. Overexpression of SIRT3 in DRG neurons by intrathecally administered LV‐SIRT3 lentivirus ameliorated neurological and mitochondrial dysfunctions. This was evidenced by the reversal of allodynia and nociceptor hyperexcitability, as well as the restoration of MMP and ATP levels. Overexpression of SIRT3 restored the inhibited mitophagy by activating the FoxO3a‐PINK1‐Parkin signaling pathway. The effects of SIRT3 overexpression, including the reversal of allodynia and nociceptor hyperexcitability, the improvement of impaired mitochondria and mitophagy, and the restoration of PINK1 and Parkin expression, were counteracted when FoxO3a siRNA was intrathecally injected.ConclusionThese results showed that SIRT3 overexpression ameliorates PDN via activation of FoxO3a‐PINK1‐Parkin‐mediated mitophagy, suggesting that SIRT3 may become an encouraging therapeutic strategy for PDN.

更新日期：2024-04-04

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