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Neuropathic Pain: the Dysfunction of Drp1, Mitochondria, and ROS Homeostasis

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Abstract

Neuropathic pain affects the physical and mental health status of patients. Due to its complex pathogenesis and the adverse reactions to medicines, its treatment remains challenging. Among all the etiologies, increasing evidence has pointed to mitochondrial dysfunction. Dynamin-related protein 1 (Drp1)–mediated mitochondrial fragmentation leads to excess ROS generation, which is implicated in the pathogenesis of neuropathic pain. However, the exact mechanism remains unclear. Studies aiming to clarify the possible pathway and relationship between Drp1, mitochondria, ROS, and neuropathic pain may identify a good treatment for neuropathic pain in the clinic. As shown in this review, dysfunction of Drp1 and ROS homeostasis plays essential roles in neuropathic pain. We summarized a Drp1-mitochondrial fission-ROS cycle that potentially functions in neuropathic pain and is regulated by posttranslational modifications and Ca2+. Additionally, we further enumerated six Drp1 inhibitors, including Mdivi-1, P110, Drp1 antisense oligodeoxynucleotides, hyperbaric oxygen, melatonin, and β-hydroxybutyrate, as potential treatments, with the aim of providing guidance for novel molecules to be used in the clinic.

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Abbreviations

Drp1:

dynamin-related protein 1

GFP:

green fluorescent protein

ROS:

reactive oxygen species

OXPHOS:

oxidative phosphorylation

NMDA:

N-methyl-d-aspartate

MD:

middle domain

GED:

GTPase effector domain

VD:

variable domain

SUMO:

small ubiquitin-like modifier

S:

serine

DNM1L:

dynamin-1-like protein

CCI:

chronic constrictive injury

ddC:

2,3-dideoxycytidine

DRG:

dorsal root ganglia

Mff:

mitochondria fission factor

Fis1:

fission protein 1

PKA:

protein kinase A

Ref-1:

redox-factor 1

NOX4:

type 4 isoform

O-GlcNAcylation:

O-linked β-N-acetylglucosaminylation

CDK1:

cyclin-dependent kinase 1

NOS:

nitric oxide synthase

mPTP:

mitochondrial permeability transition pore

SOD:

superoxide dismutase

GSH:

glutathione

Mdivi-1:

mitochondrial division inhibitor

ODN:

oligodeoxynucleotide

HBO:

hyperbaric oxygen

pAMPK:

phosphorylated AMP activated protein kinase

CaMKKβ:

calmodulin-dependent protein kinase kinase β

BHB:

β-hydroxybutyrate

KD:

ketogenic diet

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  1. Third Medical District, Lintong Rehabilitation and Convalescent Centre, Xi’an, 710600, People’s Republic of China

    Chun-Qiu Dai, Yu Guo & Xue-Yan Chu

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  1. Chun-Qiu Dai
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  2. Yu Guo
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Xue-Yan Chu had the idea for the manuscript. Yu Guo and Chun-Qiu Dai performed the literature search and data analysis. Yu Guo contributed to the drawing of figures. Chun-Qiu Dai contributed to the manuscript drafting. All authors read and approved the final manuscript.

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Correspondence to Xue-Yan Chu.

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Dai, CQ., Guo, Y. & Chu, XY. Neuropathic Pain: the Dysfunction of Drp1, Mitochondria, and ROS Homeostasis. Neurotox Res 38, 553–563 (2020). https://doi.org/10.1007/s12640-020-00257-2

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