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

• DOI: 10.1111/cns.14703
• Publication Date: 2024-04-04T11:40:23Z
• Authors: Jing Yang; Zhuoying Yu; Ye Jiang; Zixian Zhang; Yue Tian; Jie Cai; Min Wei; Yanhan Lyu; Dongsheng Yang; Shixiong Shen; Guo‐Gang Xing; Min Li
• Keywords: SIRT3; PINK1; Diabetic Neuropathy; Dorsal root ganglion

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