1. Academic Validation
  2. Inhibition of Drp1 ameliorates diabetic retinopathy by regulating mitochondrial homeostasis

Inhibition of Drp1 ameliorates diabetic retinopathy by regulating mitochondrial homeostasis

  • Exp Eye Res. 2022 Jul;220:109095. doi: 10.1016/j.exer.2022.109095.
Meng-Yuan Zhang 1 Lingpeng Zhu 2 Xun Bao 1 Tian-Hua Xie 1 Jiping Cai 1 Jian Zou 2 Wenjuan Wang 2 Shun Gu 1 Yan Li 1 Hong-Ying Li 1 Yong Yao 3 Ting-Ting Wei 4
Affiliations

Affiliations

  • 1 Department of Ophthalmology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, PR China.
  • 2 Center of Clinical Research, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, PR China.
  • 3 Department of Ophthalmology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, PR China; Department of Ophthalmology, The Affiliated Wuxi No.2 People's Hospital of Nanjing Medical University, Wuxi, PR China. Electronic address: yongyao@njmu.edu.cn.
  • 4 Center of Clinical Research, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, PR China. Electronic address: tingtingwei@njmu.edu.cn.
Abstract

Diabetic retinopathy (DR) is a potentially blinding complication resulting from diabetes mellitus (DM). Retinal vascular endothelial cells (RMECs) dysfunction occupies an important position in the pathogenesis of DR, and mitochondrial disorders play a vital role in RMECs dysfunction. However, the detailed mechanisms underlying DR-induced mitochondrial disorders in RMECs remain elusive. In the present study, we used High glucose (HG)-induced RMECs in vitro and streptozotocin (STZ)-induced Sprague-Dawley rats in vivo to explore the related mechanisms. We found that HG-induced mitochondrial dysfunction via mitochondrial Dynamin-related protein 1(Drp1)-mediated mitochondrial fission. Drp1 inhibitor, Mdivi-1, rescued HG-induced mitochondrial dysfunction. Protein Kinase Cδ (PKCδ) could induce phosphorylation of Drp1, and we found that HG induced phosphorylation of PKCδ. PKCδ Inhibitor (Go 6983) or PKCδ siRNA reversed HG-induced phosphorylation of Drp1 and further mitochondrial dysfunction. The above studies indicated that HG increases mitochondrial fission via promoting PKCδ/Drp1 signaling. Drp1 induces excessive mitochondrial fission and produces damaged mitochondrial, and Mitophagy plays a key role in clearing damaged mitochondrial. Our study showed that HG suppressed Mitophagy via inhibiting LC3B-II formation and p62 degradation. 3-MA (Autophagy Inhibitor) aggravated HG-induced RMECs damage, while rapamycin (Autophagy agonist) rescued the above phenomenon. Further studies were identified that HG inhibited Mitophagy by down-regulation of the PINK1/Parkin signaling pathway, and PINK1 siRNA aggravated HG-induced RMECs damage. Further in-depth study, we propose that Drp1 promotion of Hexokinase II (HK-II) separation from mitochondria, thus inhibiting HK-II-PINK1-mediated Mitophagy. In vivo, we found that intraretinal microvascular abnormalities (IRMA), including retinal vascular leakage, acellular capillaries, and Apoptosis were increased in STZ-induced DR rats, which were reversed by pretreatment with Mdivi-1 or Rapamycin. Altogether, our findings provide new insight into the mechanisms underlying the regulation of mitochondrial homeostasis and provide a potential treatment strategy for Diabetic retinopathy.

Keywords

Diabetic retinopathy; Drp1; Mitochondrial fission; Mitophagy; PINK1.

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