June 2021
Volume 62, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2021
Mitochondria fission and diabetic retinopathy: Role of Drp1
Author Affiliations & Notes
  • Ghulam Mohammad
    Department of Ophthalmology, Visual and Anatomical Sciences, Wayne State University School of Medicine, Detroit, Michigan, United States
  • Renu A Kowluru
    Department of Ophthalmology, Visual and Anatomical Sciences, Wayne State University School of Medicine, Detroit, Michigan, United States
  • Footnotes
    Commercial Relationships   Ghulam Mohammad, None; Renu Kowluru, None
  • Footnotes
    Support  RO1 EY014370; RO1 EY017313; RO1 EY022230
Investigative Ophthalmology & Visual Science June 2021, Vol.62, 2248. doi:
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      Ghulam Mohammad, Renu A Kowluru; Mitochondria fission and diabetic retinopathy: Role of Drp1. Invest. Ophthalmol. Vis. Sci. 2021;62(8):2248.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : In the pathogenesis of diabetic retinopathy, retinal capillary cells undergo accelerated apoptosis, and mitochondria dysfunction is considered as one of the mechanisms underlying in their death. Mitochondria are dynamic structures, and depending on the energy demand, they continuously fuse and divide. Mitochondrial fission is mediated by GTPase dynamin-related protein 1 (Drp1), and Drp1 activity is modulated by posttranslational modifications including phosphorylation and S-nitrosylation. While phosphorylation at Ser616 of Drp1 facilitates its recruitment to the surface of the mitochondria, S-nitrosylation facilitates phosphorylation at Ser616. Mitochondrial fission protein 1 (Fis1) and mitochondrial fission factor (Mff) serve as key receptors for Drp1 to promote mitochondrial fission. The aim of this study was to investigate the putative mechanisms underlying the activation of Drp1 in the development of diabetic retinopathy.

Methods : Drp1 S-nitrosylation and phosphorylation and Fis1 expression were quantified in the human retinal endothelial cells (HRECs), incubated in normal (NG) or high (HG) glucose for 96 hours by immunofluorescence microscopy and by Western blotting. Role of Drp1 in the regulation of mitochondrial fission, ROS generation and membrane depolarization, respectively, were detected using Mitotracker green, MitoSox and JC1 assays. To transition to the in vivo model, gene and protein expressions of Drp1, Fis1 and Mff were quantified by qRT- PCR and Western blotting in the retinal microvessel from streptozotocin induced-diabetic rats.

Results : Hyperglycemia elevated Drp1 S-nitrosylation and Ser616 phosphorylation, and also increased its co-localization in the mitochondrial outer membrane. Regulation of nitrosylation prevented glucose-induced phosphorylation of Drp1, and Drp1-siRNA ameliorated fragmentation of the mitochondria, superoxide production and membrane potential. Consistent with the in vitro model, retinal microvasculature from diabetic rats, compared to the age-matched nondiabetic rats, had increased Drp1-Ser616 phosphorylation and Fis1 and Mff expressions.

Conclusions : Due to posttranslational modifications of Drp1 in hyperglycemia, its translocation inside the mitochondria is increased, and mitochondrial integrity is disturbed. Thus, targeting Drp1 may serve as a potential therapy to halt the development of diabetic retinopathy.

This is a 2021 ARVO Annual Meeting abstract.

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