Dataset Information

Adaptor Protein p66Shc: A Link Between Cytosolic and Mitochondrial Dysfunction in the Development of Diabetic Retinopathy.

ABSTRACT:

Aims

Diabetes increases oxidative stress in the retina and dysfunctions their mitochondria, accelerating capillary cell apoptosis. A 66?kDa adaptor protein, p66Shc, is considered as a sensor of oxidative stress-induced apoptosis. In the pathogenesis of diabetic retinopathy, a progressive disease, reactive oxygen species (ROS) production by activation of a small molecular weight G-protein (Ras-related C3 botulinum toxin substrate 1 [Rac1])-Nox2 signaling precedes mitochondrial damage. Rac1 activation is facilitated by guanine exchange factors (GEFs), and p66Shc increases Rac1-specific GEF activity of Son of Sevenless 1 (Sos1). p66Shc also possesses oxidoreductase activity and can directly stimulate mitochondrial ROS generation. Our aim was to investigate the role of p66Shc in the development of diabetic retinopathy and mechanism of its transcription.

Results

High glucose increased p66Shc expression in human retinal endothelial cells, and elevated acetylated histone 3 lysine 9 (H3K9) levels and transcriptional factor p53 binding at its promoter. Glucose also augmented interactions between Rac1 and Sos1 and activated Rac1-Nox2. Phosphorylation of p66Shc was increased, allowing it to interact with peptidyl prolyl isomerase to facilitate its localization inside the mitochondria, culminating in mitochondrial damage. P66shc-small interfering RNA (siRNA) inhibited glucose-induced Rac1 activation and mitochondrial damage. Similar results are observed in retinal microvessels from diabetic rats.

Innovation

This is the first report identifying the role of p66Shc in the development of diabetic retinopathy and implicating increased histone acetylation in its transcriptional regulation.

Conclusion

Thus, p66Shc has dual role in the development of diabetic retinopathy; its regulation in the early stages of the disease should impede Rac1-ROS production and, in the later stages, prevent mitochondrial damage and initiation of a futile cycle of free radicals.

SUBMITTER: Mishra M

PROVIDER: S-EPMC6459280 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Publications

Adaptor Protein p66Shc: A Link Between Cytosolic and Mitochondrial Dysfunction in the Development of Diabetic Retinopathy.

Mishra Manish M Duraisamy Arul J AJ Bhattacharjee Sudarshan S Kowluru Renu A RA

Antioxidants & redox signaling 20181003 13

<h4>Aims</h4>Diabetes increases oxidative stress in the retina and dysfunctions their mitochondria, accelerating capillary cell apoptosis. A 66 kDa adaptor protein, p66Shc, is considered as a sensor of oxidative stress-induced apoptosis. In the pathogenesis of diabetic retinopathy, a progressive disease, reactive oxygen species (ROS) production by activation of a small molecular weight G-protein (Ras-related C3 botulinum toxin substrate 1 [Rac1])-Nox2 signaling precedes mitochondrial damage. Rac ...[more]

PMID: 30105917

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Project description:PurposeWe aimed to investigate the prevalence of diabetic retinopathy (DR) in patients with diabetic foot ulcer (DFU) and elucidate the association between DR and DFU severities and their shared risk factors.MethodsA retrospective review was conducted on DFU patients who underwent ophthalmic and vascular examinations within 6 months; 100 type 2 diabetic patients with DFU were included. The medical records of 2496 type 2 diabetic patients without DFU served as control data. DR prevalence and severity were assessed in DFU patients. DFU patients were compared with the control group regarding each clinical variable. Additionally, DFU patients were divided into two groups according to DR severity and compared.ResultsOut of 100 DFU patients, 90 patients (90%) had DR and 55 (55%) had proliferative DR (PDR). There was no significant association between DR and DFU severities (R = 0.034, p = 0.734). A multivariable analysis comparing type 2 diabetic patients with and without DFUs showed that the presence of DR [OR, 226.12; 95% confidence interval (CI), 58.07-880.49; p < 0.001] and proliferative DR [OR, 306.27; 95% CI, 64.35-1457.80; p < 0.001), higher HbA1c (%, OR, 1.97, 95% CI, 1.46-2.67; p < 0.001), higher serum creatinine (mg/dL, OR, 1.62, 95% CI, 1.06-2.50; p = 0.027), older age (years, OR, 1.12; 95% CI, 1.06-1.17; p < 0.001), higher pulse pressure (mmHg, OR, 1.03; 95% CI, 1.00-1.06; p = 0.025), lower cholesterol (mg/dL, OR, 0.94; 95% CI, 0.92-0.97; p < 0.001), lower BMI (kg/m2, OR, 0.87, 95% CI, 0.75-1.00; p = 0.044) and lower hematocrit (%, OR, 0.80, 95% CI, 0.74-0.87; p < 0.001) were associated with DFUs. In a subgroup analysis of DFU patients, the PDR group had a longer duration of diabetes mellitus, higher serum BUN, and higher serum creatinine than the non-PDR group. In the multivariable analysis, only higher serum creatinine was associated with PDR in DFU patients (OR, 1.37; 95% CI, 1.05-1.78; p = 0.021).ConclusionsDiabetic retinopathy is prevalent in patients with DFU and about half of DFU patients had PDR. No significant association was found in terms of the severity of these two diabetic complications. To prevent blindness, patients with DFU, and especially those with high serum creatinine, should undergo retinal examinations for timely PDR diagnosis and management.

Project description:Macroautophagy/autophagy has emerged as a central process in lymphocyte homeostasis, activation and differentiation. Based on our finding that the p66 isoform of SHC1 (p66SHC) pro-apoptotic ROS-elevating SHC family adaptor inhibits MTOR signaling in these cells, here we investigated the role of p66SHC in B-cell autophagy. We show that p66SHC disrupts mitochondrial function through its CYCS (cytochrome c, somatic) binding domain, thereby impairing ATP production, which results in AMPK activation and enhanced autophagic flux. While p66SHC binding to CYCS is sufficient for triggering apoptosis, p66SHC-mediated autophagy additionally depends on its ability to interact with membrane-associated LC3-II through a specific binding motif within its N terminus. Importantly, p66SHC also has an impact on mitochondria homeostasis by inducing mitochondrial depolarization, protein ubiquitination at the outer mitochondrial membrane, and local recruitment of active AMPK. These events initiate mitophagy, whose full execution relies on the role of p66SHC as an LC3-II receptor which brings phagophore membranes to mitochondria. Importantly, p66SHC also promotes hypoxia-induced mitophagy in B cells. Moreover, p66SHC deficiency enhances B cell differentiation to plasma cells, which is controlled by intracellular ROS levels and the hypoxic germinal center environment. The results identify mitochondrial p66SHC as a novel regulator of autophagy and mitophagy in B cells and implicate p66SHC-mediated coordination of autophagy and apoptosis in B cell survival and differentiation. Abbreviations: ACTB: actin beta; AMPK: AMP-activated protein kinase; ATP: adenosine triphosphate; ATG: autophagy-related; CYCS: cytochrome c, somatic; CLQ: chloroquine; COX: cyclooxygenase; CTR: control; GFP: green fluorescent protein; HIFIA/Hif alpha: hypoxia inducible factor 1 subunit alpha; IMS: intermembrane space; LIR: LC3 interacting region; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MTOR/mTOR: mechanistic target of rapamycin kinase; OA: oligomycin and antimycin A; OMM: outer mitochondrial membrane; PHB: prohibitin; PBS: phosphate-buffered saline; PINK1: PTEN induced putative kinase 1; RFP: red fluorescent protein; ROS: reactive oxygen species; SHC: src Homology 2 domain-containing transforming protein; TMRM: tetramethylrhodamine, methyl ester; TOMM: translocase of outer mitochondrial membrane; ULK1: unc-51 like autophagy activating kinase 1; WT: wild-type.

Dataset Information

Adaptor Protein p66Shc: A Link Between Cytosolic and Mitochondrial Dysfunction in the Development of Diabetic Retinopathy.

Aims

Results

Innovation

Conclusion

Publications

Adaptor Protein p66Shc: A Link Between Cytosolic and Mitochondrial Dysfunction in the Development of Diabetic Retinopathy.

Similar Datasets

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