Mechanistic dissection of diabetic retinopathy using the protein-metabolite interactome

Ambrose Teru Patrick, Weilue He, Joshua Madu, Srinivas R. Sripathi, Seulggie Choi, Kook Lee, Faith Pwaniyibo Samson, Folami L. Powell, Manuela Bartoli, Donghyun Jee, Diana R. Gutsaeva, Wan Jin Jahng

Research output: Contribution to journalArticle

Abstract

Purpose: The current study aims to determine the molecular mechanisms of diabetic retinopathy (DR) using the protein-protein interactome and metabolome map. We examined the protein network of novel biomarkers of DR for direct (physical) and indirect (functional) interactions using clinical target proteins in different models. Methods: We used proteomic tools including 2-dimensional gel electrophoresis, mass spectrometry analysis, and database search for biomarker identification using in vivo murine and human model of diabetic retinopathy and in vitro model of oxidative stress. For the protein interactome and metabolome mapping, various bioinformatic tools that include STRING and OmicsNet were used. Results: We uncovered new diabetic biomarkers including prohibitin (PHB), dynamin 1, microtubule-actin crosslinking factor 1, Toll-like receptor (TLR 7), complement activation, as well as hypothetical proteins that include a disintegrin and metalloproteinase (ADAM18), vimentin III, and calcium-binding C2 domain-containing phospholipid-binding switch (CAC2PBS) using a proteomic approach. Proteome networks of protein interactions with diabetic biomarkers were established using known DR-related proteome data. DR metabolites were interconnected to establish the metabolome map. Our results showed that mitochondrial protein interactions were changed during hyperglycemic conditions in the streptozotocin-treated murine model and diabetic human tissue. Conclusions: Our interactome mapping suggests that mitochondrial dysfunction could be tightly linked to various phases of DR pathogenesis including altered visual cycle, cytoskeletal remodeling, altered lipid concentration, inflammation, PHB depletion, tubulin phosphorylation, and altered energy metabolism. The protein-metabolite interactions in the current network demonstrate the etiology of retinal degeneration and suggest the potential therapeutic approach to treat DR.

Original languageEnglish (US)
JournalJournal of Diabetes and Metabolic Disorders
DOIs
StateAccepted/In press - 2020

Keywords

  • ADAM18
  • CAC2PBS
  • Diabetic retinopathy
  • Interactome
  • Metabolome
  • Mitochondria
  • Prohibitin
  • Proteomics
  • Tubulin

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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