Journal Article

Hyperglycemia‐induced Sirt3 downregulation increases microglial aerobic glycolysis and inflammation in diabetic neuropathic pain pathogenesis

Kong, Erliang, Song, Honghao, Deng, Mengqiu, Wei, Huawei, Ding, Ruifeng, Yuan, Hongbin, Lu, Jinfang, Han, Chaofeng, Chen, Dashuang, Chu, Ruitong, Li, Yongchang, Yang, Mei, Hua, Tong, Wang, Haowei, Zhang, Ping

2024

Overview

Background Hyperglycemia‐induced neuroinflammation significantly contributes to diabetic neuropathic pain (DNP), but the underlying mechanisms remain unclear. Objective To investigate the role of Sirt3, a mitochondrial deacetylase, in hyperglycemia‐induced neuroinflammation and DNP and to explore potential therapeutic interventions. Method and Results Here, we found that Sirt3 was downregulated in spinal dorsal horn (SDH) of diabetic mice by RNA‐sequencing, which was further confirmed at the mRNA and protein level. Sirt3 deficiency exacerbated hyperglycemia‐induced neuroinflammation and DNP by enhancing microglial aerobic glycolysis in vivo and in vitro. Overexpression of Sirt3 in microglia alleviated inflammation by reducing aerobic glycolysis. Mechanistically, high‐glucose stimulation activated Akt, which phosphorylates and inactivates FoxO1. The inactivation of FoxO1 diminished the transcription of Sirt3. Besides that, we also found that hyperglycemia induced Sirt3 degradation via the mitophagy‐lysosomal pathway. Blocking Akt activation by GSK69093 or metformin rescued the degradation of Sirt3 protein and transcription inhibition of Sirt3 mRNA, which substantially diminished hyperglycemia‐induced inflammation. Metformin in vivo treatment alleviated neuroinflammation and diabetic neuropathic pain by rescuing hyperglycemia‐induced Sirt3 downregulation. Conclusion Hyperglycemia induces metabolic reprogramming and inflammatory activation in microglia through the regulation of Sirt3 transcription and degradation. This novel mechanism identifies Sirt3 as a potential drug target for treating DNP. Li et al. have addressed the critical role of hyperglycemia‐induced neuroinflammation in the pathogenesis of diabetic neuropathic pain (DNP), a significant and growing global health concern due to the rising prevalence of diabetes. Metformin can decrease neuroinflammation and DNP, and this effect depends on its regulation of Sirt3 protein level.

• Publisher: John Wiley & Sons, Inc
• Subject: AKT protein / Akt/FoxO1 / Animals / Antibodies / Degradation / Diabetes / Diabetes mellitus / Diabetes Mellitus, Experimental - complications / Diabetes Mellitus, Experimental - metabolism / diabetic neuropathic pain / Diabetic Neuropathies - metabolism / Diabetic neuropathy / Dorsal horn / Down-regulation / Down-Regulation - drug effects / Down-Regulation - physiology / Enzymes / FOXO1 protein / Gene regulation / Glucose / Glycolysis / Glycolysis - drug effects / Glycolysis - physiology / Hyperalgesia / Hyperglycemia / Hyperglycemia - metabolism / Inflammation / Inflammation - metabolism / Laboratory animals / Male / Metabolic rate / Metabolism / Metformin / Metformin - pharmacology / Mice / Mice, Inbred C57BL / Microglia / Microglia - drug effects / Microglia - metabolism / Mitophagy / Molecular weight / Nervous system / Neuralgia / neuroinflammation / Neuroinflammatory Diseases - etiology / Neuroinflammatory Diseases - metabolism / Oxidative stress / Pain / Pathogenesis / Protein deficiency / Proteins / Reagents / Sirt3 / Sirtuin 3 - genetics / Sirtuin 3 - metabolism / Therapeutic applications / Therapeutic targets / Transcription / Transcription activation