TY - JOUR
T1 - Mechanistic dissection of diabetic retinopathy using the protein-metabolite interactome
AU - Patrick, Ambrose Teru
AU - He, Weilue
AU - Madu, Joshua
AU - Sripathi, Srinivas R.
AU - Choi, Seulggie
AU - Lee, Kook
AU - Samson, Faith Pwaniyibo
AU - Powell, Folami L.
AU - Bartoli, Manuela
AU - Jee, Donghyun
AU - Gutsaeva, Diana R.
AU - Jahng, Wan Jin
N1 - Funding Information:
The current research was supported in part by Research Assistantship and Teaching Assistantship from the American University of Nigeria.
Publisher Copyright:
© 2020, Springer Nature Switzerland AG.
PY - 2020/12
Y1 - 2020/12
N2 - 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.
AB - 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.
KW - ADAM18
KW - CAC2PBS
KW - Diabetic retinopathy
KW - Interactome
KW - Metabolome
KW - Mitochondria
KW - Prohibitin
KW - Proteomics
KW - Tubulin
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U2 - 10.1007/s40200-020-00570-9
DO - 10.1007/s40200-020-00570-9
M3 - Article
AN - SCOPUS:85086707458
SN - 2251-6581
VL - 19
SP - 829
EP - 848
JO - Journal of Diabetes and Metabolic Disorders
JF - Journal of Diabetes and Metabolic Disorders
IS - 2
ER -