Department of Anesthesiology, Peking University Third Hospital, Beijing, China.
Neuroscience Research Institute, Peking University, Beijing, China.
CNS Neurosci Ther. 2024 Apr;30(4):e14703. doi: 10.1111/cns.14703.
Painful 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.
In 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.
We 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.
These 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.
痛性糖尿病周围神经病变（PDN）是糖尿病的一种常见并发症。先前的研究表明，线粒体功能障碍在 PDN 的发展中起作用，但其发病机制和机制尚未得到充分研究。
在这项研究中，我们使用高脂肪饮食/低剂量链脲佐菌素诱导的大鼠作为 2 型糖尿病模型。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感觉神经传导速度研究用于评估周围神经病变。线粒体膜电位（MMP）、ATP、组织活性氧和透射电子显微镜用于评估 DRG 中线粒体的功能和形态。实时 PCR、western blot 和免疫荧光用于研究机制。
我们发现 PDN 大鼠中积累了受损的线粒体，并且自噬受到抑制。线粒体中 NAD 依赖性去乙酰化酶 Sirtuin 3（SIRT3）的表达受到抑制。通过鞘内给予 LV-SIRT3 慢病毒过表达 DRG 神经元中的 SIRT3 可改善神经和线粒体功能障碍。这表现在痛觉过敏和伤害感受器过度兴奋的逆转，以及 MMP 和 ATP 水平的恢复。SIRT3 的过表达通过激活 FoxO3a-PINK1-Parkin 信号通路恢复了被抑制的自噬。当 FoxO3a siRNA 鞘内注射时，SIRT3 过表达的所有作用，包括痛觉过敏和伤害感受器过度兴奋的逆转、受损线粒体和自噬的改善以及 PINK1 和 Parkin 表达的恢复，都被抵消了。
这些结果表明，SIRT3 过表达通过激活 FoxO3a-PINK1-Parkin 介导的自噬来改善 PDN，这表明 SIRT3 可能成为治疗 PDN 的一种有希望的治疗策略。
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