Targeted up-regulation of Drp1 in dorsal horn attenuates neuropathic pain hypersensitivity by increasing mitochondrial fission

Zhang, Kun-Long; Li, Shu-Jiao; Pu, Xue-Yin; Wu, Feifei; Liu, Hui; Wang, Ruiqing; Liu, Bo-Zhi; Li, Ze; Li, Kaifeng; Qian, Niansong; Yang, Yanling; Yuan, Hua; Wang, Yayun

doi:10.1016/j.redox.2021.102216

Cited by 22 publications

(8 citation statements)

References 92 publications

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“…In our study, DRG neurons in PDN rats had fragmented and vacuolated mitochondria. Similar morphological changes in mitochondria were observed in DRG in type 1 diabetes mellitus (T1DM) rats 31 . Since MMP is a driving force for the transport of ions and proteins which are necessary for healthy mitochondria, mitochondrial function can be assessed by monitoring MMP changes 32 .…”

Section: Discussionmentioning

confidence: 64%

“…Similar morphological changes in mitochondria were observed in DRG in type 1 diabetes mellitus (T1DM) rats. 31 Since MMP is a driving force for the transport of ions and proteins which are necessary for healthy mitochondria, mitochondrial function can be assessed by monitoring MMP changes. 32 In ATP generation, mitochondria rely on the stability of the MMP.…”

Section: Discussionmentioning

confidence: 99%

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

Yang,

Yu,

Jiang

et al. 2024

CNS Neurosci Ther

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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.

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Section: Discussionmentioning

confidence: 64%

Section: Discussionmentioning

confidence: 99%

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

Yang,

Yu,

Jiang

et al. 2024

CNS Neurosci Ther

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“…The removal of mitochondrial calcium uniporter has been shown to prevent painful diabetic neuropathy by restoring both the morphology and dynamics of mitochondria [41]. Another study demonstrated that the targeted up-regulation of Drp1 in the dorsal horn could attenuate NP hypersensitivity by increasing mitochondrial ssion [42]. SIRT3 regulates the balance between mitochondrial ssion and fusion and is involved in the etiology of a variety of diseases, such as Huntington's disease [43] and kidney injury [44].…”

Section: Discussionmentioning

confidence: 99%

Deacetylase SIRT3 alleviates neuropathic pain by improving mitochondrial fission and fusion in spinal dorsal horn neurons

Sun,

Yang,

Xie

et al. 2023

Preprint

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Background: The mitochondria contribute to neuropathic pain (NP) by regulating mitochondrial function and cellular redox capacity. Sirtuin3 (SIRT3), an NAD+-dependent deacetylase primarily expressed in the mitochondria, is involved in the regulation of mitochondrial proteins. This study aimed to investigate the effect of SIRT3 within succinate dehydrogenase (SDH) on mitochondrial function and NP in mice with chronic constriction injury (CCI). Methods: Wild-type littermates underwent CCI surgery at 8-10 weeks postnatally. Western-blot and immunofluorescence was applied to detect the changes of SIRT3 protein in SDH after CCI. Lentivirus-SIRT3 and SIRT3-knockout mice (SIRT3-/-) were used to overexpress or knockdown of SIRT3. Mitochondrial fluorescence probe and electron microscope were used to observe the changes of mitochondrial morphology. ROS fluorescent probe dihydroethidium (DHE) and antioxidant enzyme kit were employed to determine the level of oxidative stress in SDH. Results: SIRT3 protein levels were significantly decreased in CCI mice. Overexpression of spinal SIRT3 by intrathecal injection of LV-SIRT3 attenuates pain hypersensitivity in CCI mice. Transgenic SIRT3-knockout mice (SIRT3-/-) show pain allergy in the physiological state. SIRT3 plays a major role in the regulation of mitochondrial fusion protein expression in optic atrophy 1 (OPA1). Ultrastructural analysis showed that CCI and SIRT3-/- mice induced mitochondria with smaller perimeters, areas, and interconnectivity in the SDH. CCI and SIRT3 deletion significantly increased oxidative stress, as evidenced by increased ROS levels and decreased activity of antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT) in the SDH. Conclusion: Taken together, these results suggest that SIRT3 attenuates pain hypersensitivity in mice by regulating dynamic changes and oxidative stress in mitochondria.

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“…Finally, the ultrastructural characteristics of hippocampal mitochondria were observed using TEM (HT7700‐SS, HITACHI, Japan). Referring to previous studies, 21 , 22 three parameters (number of mitochondria /100 um 2 , number of dumbbell‐shaped mitochondria /100 um 2 , and mitochondrial vacuole area /um 2 ) were analyzed using ImageJ software to assess mitochondrial abnormalities. Each mouse was photographed in three randomly selected views.…”

Section: Methodsmentioning

confidence: 99%

The cold‐inducible RNA‐binding protein—Thioredoxin 1 pathway ameliorates mitochondrial dysfunction and mitochondrial dynamin‐related protein 1 level in the hippocampus of aged mice with perioperative neurocognitive dysfunction

Huang,

Zhu,

Liu

et al. 2023

CNS Neurosci Ther

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BackgroundAs a multi‐disease model, neuroinflammation, mitochondrial dysfunction, and oxidative stress might be involved in the pathogenic process of perioperative neurocognitive dysfunction (PND). Dynamin‐related protein 1 (Drp1) could mediate mitochondrial fission and play important roles in mitochondrial dynamic homeostasis and mitochondria function. The Drp1 may be involved in PND development. The cold‐inducible RNA‐binding protein (Cirbp) could bind to the 3’‐UTR of the thioredoxin 1 (Trx1) mRNA, control oxidative stress, and improve mitochondrial function. In this study, we hypothesized that the Cirbp‐Trx1 pathway could ameliorate mitochondrial dysfunction and Drp1 levels in PND mice.MethodsDifferentially expressed genes were screened using the Gene Expression Omnibus (GEO) database GSE95426 and validated using PCR. Eighteen‐month‐old C57BL/6 mice were subjected to tibial fracture surgery to generate a PND model. Cirbp was upregulated by hippocampal stereotaxic injections of over‐Cirbp plasmid according to the manufacturer's instructions for the in vivo DNA transfection reagent. Cirbp expression was measured using western blot (WB) and immunofluorescence (IF). The Morris water maze (MWM) was used to assess cognitive function. After behavioral testing, the hippocampal tissue was extracted to examine changes in mitochondrial Drp1, mitochondrial function, neuroinflammation, and oxidative stress.ResultsDifferential gene screening showed that Cirbp expression was significantly downregulated (fold change >1.5, p = 0.003272) in the PND model. In this study, we also found that Cirbp protein levels were downregulated, accompanied by an impairment of cognition, a decrease in superoxide dismutase (SOD) activity, and an increase in malondialdehyde (MDA) content, mitochondrial Drp1 levels, neuroinflammation, and apoptosis. Cirbp overexpression increased Trx1 protein levels and reversed the damage. However, this protective effect was abolished by PX‐12 treatment with a Trx1 inhibitor.ConclusionsThe Cirbp‐Trx1 pathway may regulate mitochondrial dysfunction and mitochondrial Drp1 expression in the hippocampus of PND mice to ameliorate cognitive dysfunction.

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Targeted up-regulation of Drp1 in dorsal horn attenuates neuropathic pain hypersensitivity by increasing mitochondrial fission

Cited by 22 publications

References 92 publications

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

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

Deacetylase SIRT3 alleviates neuropathic pain by improving mitochondrial fission and fusion in spinal dorsal horn neurons

The cold‐inducible RNA‐binding protein—Thioredoxin 1 pathway ameliorates mitochondrial dysfunction and mitochondrial dynamin‐related protein 1 level in the hippocampus of aged mice with perioperative neurocognitive dysfunction

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