Targeted up-regulation of Drp1 in dorsal horn attenuates neuropathic pain hypersensitivity by increasing mitochondrial fission
Kun-Long Zhang,
Shu-Jiao Li,
Xue-Yin Pu,
Fei-Fei Wu,
Hui Liu,
Rui-Qing Wang,
Bo-Zhi Liu,
Ze Li,
Kai-Feng Li,
Nian-Song Qian,
Yan-Ling Yang,
Hua Yuan,
Ya-Yun Wang
Affiliations
Kun-Long Zhang
Specific Lab for Mitochondrial Plasticity Underlying Nervous System Diseases, National Demonstration Center for Experimental Preclinical Medicine Education, The Fourth Military Medical University, Xi'an, 710032, China; Department of Rehabilitation Medicine, Xi-Jing Hospital, The Fourth Military Medical University, Xi'an, 710032, China
Shu-Jiao Li
Specific Lab for Mitochondrial Plasticity Underlying Nervous System Diseases, National Demonstration Center for Experimental Preclinical Medicine Education, The Fourth Military Medical University, Xi'an, 710032, China
Xue-Yin Pu
Specific Lab for Mitochondrial Plasticity Underlying Nervous System Diseases, National Demonstration Center for Experimental Preclinical Medicine Education, The Fourth Military Medical University, Xi'an, 710032, China
Fei-Fei Wu
Specific Lab for Mitochondrial Plasticity Underlying Nervous System Diseases, National Demonstration Center for Experimental Preclinical Medicine Education, The Fourth Military Medical University, Xi'an, 710032, China
Hui Liu
Department of Human Anatomy, Yan-An University, Yan'an, 716000, China
Rui-Qing Wang
Department of Human Anatomy, Yan-An University, Yan'an, 716000, China
Bo-Zhi Liu
Specific Lab for Mitochondrial Plasticity Underlying Nervous System Diseases, National Demonstration Center for Experimental Preclinical Medicine Education, The Fourth Military Medical University, Xi'an, 710032, China
Ze Li
Specific Lab for Mitochondrial Plasticity Underlying Nervous System Diseases, National Demonstration Center for Experimental Preclinical Medicine Education, The Fourth Military Medical University, Xi'an, 710032, China
Kai-Feng Li
Specific Lab for Mitochondrial Plasticity Underlying Nervous System Diseases, National Demonstration Center for Experimental Preclinical Medicine Education, The Fourth Military Medical University, Xi'an, 710032, China
Nian-Song Qian
Department of Oncology, First Medical Center, The General Hospital of the People's Liberation Army, Beijing, 100000, China
Yan-Ling Yang
Department of Liver and Gallbladder Surgery, Xi-Jing Hospital, The Fourth Military Medical University, Xi'an, 710032, China; Corresponding author. Director of Department of Rehabilitation Medicine, Xi-Jing Hospital, The Fourth Military Medical University, Xi'an, 710032, China.
Hua Yuan
Department of Rehabilitation Medicine, Xi-Jing Hospital, The Fourth Military Medical University, Xi'an, 710032, China; Corresponding author. Vice director of Department of Liver and gallbladder surgery, Xi-Jing Hospital, The Fourth Military Medical University, Xi'an, 710032, China.
Ya-Yun Wang
Specific Lab for Mitochondrial Plasticity Underlying Nervous System Diseases, National Demonstration Center for Experimental Preclinical Medicine Education, The Fourth Military Medical University, Xi'an, 710032, China; State Key Laboratory of Military Stomatology, School of Stomatology, The Fourth Military Medical University, Xi'an, 710032, China; Corresponding author. Principle Investigator of Specific Lab for Mitochondrial Plasticity Underlying Nervous System Diseases, Director of National Demonstration Center for Experimental Preclinical Medicine Education, The Fourth Military Medical University, Xi'an, 710032, China.
Mitochondria play an essential role in pathophysiology of both inflammatory and neuropathic pain (NP), but the mechanisms are not yet clear. Dynamin-related protein 1 (Drp1) is broadly expressed in the central nervous system and plays a role in the induction of mitochondrial fission process. Spared nerve injury (SNI), due to the dysfunction of the neurons within the spinal dorsal horn (SDH), is the most common NP model. We explored the neuroprotective role of Drp1 within SDH in SNI. SNI mice showed pain behavior and anxiety-like behavior, which was associated with elevation of Drp1, as well as increased density of mitochondria in SDH. Ultrastructural analysis showed SNI induced damaged mitochondria into smaller perimeter and area, tending to be circular. Characteristics of vacuole in the mitochondria further showed SNI induced the increased number of vacuole, widened vac-perimeter and vac-area. Stable overexpression of Drp1 via AAV under the control of the Drp1 promoter by intraspinal injection (Drp1 OE) attenuated abnormal gait and alleviated pain hypersensitivity of SNI mice. Mitochondrial ultrastructure analysis showed that the increased density of mitochondria induced by SNI was recovered by Drp1 OE which, however, did not change mitochondrial morphology and vacuole parameters within SDH. Contrary to Drp1 OE, down-regulation of Drp1 in the SDH by AAV-Drp1 shRNA (Drp1 RNAi) did not alter painful behavior induced by SNI. Ultrastructural analysis showed the treatment by combination of SNI and Drp1 RNAi (SNI + Drp1 RNAi) amplified the damages of mitochondria with the decreased distribution density, increased perimeter and area, as well as larger circularity tending to be more circular. Vacuole data showed SNI + Drp1 RNAi increased vacuole density, perimeter and area within the SDH mitochondria. Our results illustrate that mitochondria within the SDH are sensitive to NP, and targeted mitochondrial Drp1 overexpression attenuates pain hypersensitivity. Drp1 offers a novel therapeutic target for pain treatment.
