Sirt3 regulates mitophagy level to promote diabetic corneal epithelial wound healing

Hu, Jianzhang; Kan, Tong; Hu, Xinying

doi:10.1016/j.exer.2019.02.011

Cited by 32 publications

(20 citation statements)

References 52 publications

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“…These findings are consistent with the conclusion that hyperglycemia leads to reduced mitochondrial bioenergetics in renal tubules and mesangial cells in diabetic nephropathy 44 and in epithelial cells in diabetic keratopathy. 21 We further demonstrated that the topical administration of mitochondria-targeted antioxidants significantly attenuated corneal edema and endothelial cell loss in diabetic mice. Previous studies have shown that mitochondrial function can be mediated by prolonged activation of ER stress.…”

Section: Discussionmentioning

confidence: 77%

Pathogenic Role of Endoplasmic Reticulum Stress in Diabetic Corneal Endothelial Dysfunction

Chen

Zhang

Xue

et al. 2022

Invest. Ophthalmol. Vis. Sci.

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Purpose Progressive corneal edema and endothelial cell loss represent the major corneal complications observed in diabetic patients after intraocular surgery. However, the underlying pathogenesis and potential treatment remain incompletely understood. Methods We used streptozotocin-induced type 1 diabetic mice and db/db type 2 diabetic mice as diabetic animal models. These mice were treated with the endoplasmic reticulum (ER) stress agonist thapsigargin; 60-mmHg intraocular pressure (IOP) with the ER stress antagonist 4-phenylbutyric acid (4-PBA); mitochondria-targeted antioxidant SkQ1; or reactive oxygen species scavenger N -acetyl- l -cysteine (NAC). Corneal thickness and endothelial cell density were measured before and after treatment. Human corneal endothelial cells were treated with high glucose with or without 4-PBA. The expression of corneal endothelial- and ER stress–related genes was detected by western blot and immunofluorescence staining. Mitochondrial bioenergetics were measured with an Agilent Seahorse XFp Analyzer. Results In diabetic mice, the appearance of ER stress preceded morphological changes in the corneal endothelium. The persistent ER stress directly caused corneal edema and endothelial cell loss in normal mice. Pharmacological inhibition of ER stress was sufficient to mitigate corneal edema and endothelial cell loss in both diabetic mice after high IOP treatment. Mechanistically, inhibiting ER stress ameliorated the hyperglycemia-induced mitochondrial bioenergetic deficits and improved the barrier and pump functional recovery of the corneal endothelium. When compared with NAC, 4-PBA and SkQ1 exhibited better improvement of corneal edema and endothelial cell loss in diabetic mice. Conclusions Hyperglycemia-induced ER stress contributes to the dysfunction of diabetic corneal endothelium, and inhibiting ER stress may offer therapeutic potential by improving mitochondrial bioenergetics.

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Section: Discussionmentioning

confidence: 77%

Pathogenic Role of Endoplasmic Reticulum Stress in Diabetic Corneal Endothelial Dysfunction

Chen

Zhang

Xue

et al. 2022

Invest. Ophthalmol. Vis. Sci.

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“… 32 The inhibition of PTEN is being considered as a conceivable drug target to treat diabetes. In addition, studies have reported Sirt3 can regulate mitophagy level to promote diabetic corneal epithelial wound healing 33 ; therefore, mitophagy has also become an entry point for diabetic keratopathy.…”

Section: Discussionmentioning

confidence: 99%

PTEN Inhibition Facilitates Diabetic Corneal Epithelial Regeneration by Reactivating Akt Signaling Pathway

Wang

et al. 2020

Trans. Vis. Sci. Tech.

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Purpose To investigate the contribution of phosphatase and tensin homologue (PTEN) on the delayed epithelial regeneration and impaired Akt activation in diabetic mice. Methods The expression of PTEN on cornea was compared between normal and diabetic mice. The corneal epithelial and nerve regeneration rate was evaluated in diabetic mice after the treatment with PTEN small interfering RNA (siRNA), PTEN inhibitors, or Akt inhibitor. The reactivation of epithelial regeneration-related signaling, including phosphorylated ( p )-Akt, p -Stat3, Sirt1, and Parkin, were assessed with Western blot and immunofluorescence staining. The effects of PTEN inhibition on cellular proliferation and migration were further evaluated in cultured mouse corneal epithelial cells. Results PTEN messenger RNA and protein levels exhibited up-regulation in diabetic cornea. Upon central epithelial debridement, the epithelial regeneration rate was significantly promoted in diabetic mice with the treatment of PTEN inhibition than that of vehicle control ( P < 0.05), which accompanied with the recovered levels of p -Akt, p -Stat3, Sirt1, and Parkin. However, the promotion of diabetic corneal epithelial regeneration rate and Akt reactivation was completed reversed by Akt inhibitor. In vitro, PTEN inhibition promoted their migration, but not the proliferation capacity. In addition, PTEN inhibitor treatment also improved the recovery of corneal nerve fiber density and sensitivity that was impaired in diabetic mice. Conclusions Elevated PTEN expression contributes to the impaired corneal epithelial regeneration and Akt activation in diabetic mice, which can be improved with PTEN inhibition. Translational Relevance Our study suggests that PTEN inhibition may serve as a new strategy for restoring the impaired corneal epithelial regeneration ability in patients with diabetes.

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“…When mitochondria do not recover from damage, mitophagy signaling is activated [ 68 ]. There are reports that SIRT3 upregulated mitophagy key proteins, such as parkin, under stress conditions [ 126 ]. Indeed, it was determined that SIRT3 physically interacts with PINK1 and parkin and that its overexpression reduced the amount of acetylation of these proteins [ 127 ].…”

Section: Sirtuinsmentioning

confidence: 99%

“…Indeed, it was determined that SIRT3 physically interacts with PINK1 and parkin and that its overexpression reduced the amount of acetylation of these proteins [ 127 ]. Additionally, it was suggested that the activation of mitophagy by stressors is mediated through deacetylation of FOXO3a [ 126 ]. In SIRT3 -/- mouse myocardia cells, impairment of Parkin-mediated mitophagy was detected due to the increase of the complex p53/parkin, which avoids parkin mitochondrial translocation [ 128 ].…”

Section: Sirtuinsmentioning

confidence: 99%

Sirtuins Modulation: A Promising Strategy for HIV-Associated Neurocognitive Impairments

Figarola-Centurión

Escoto-Delgadillo

González-Enríquez

et al. 2022

IJMS

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HIV-Associated neurocognitive disorder (HAND) is one of the major concerns since it persists in 40% of this population. Nowadays, HAND neuropathogenesis is considered to be caused by the infected cells that cross the brain–blood barrier and produce viral proteins that can be secreted and internalized into neurons leading to disruption of cellular processes. The evidence points to viral proteins such as Tat as the causal agent for neuronal alteration and thus HAND. The hallmarks in Tat-induced neurodegeneration are endoplasmic reticulum stress and mitochondrial dysfunction. Sirtuins (SIRTs) are NAD+-dependent deacetylases involved in mitochondria biogenesis, unfolded protein response, and intrinsic apoptosis pathway. Tat interaction with these deacetylases causes inhibition of SIRT1 and SIRT3. Studies revealed that SIRTs activation promotes neuroprotection in neurodegenerative diseases such Alzheimer’s and Parkinson’s disease. Therefore, this review focuses on Tat-induced neurotoxicity mechanisms that involve SIRTs as key regulators and their modulation as a therapeutic strategy for tackling HAND and thereby improving the quality of life of people living with HIV.

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Sirt3 regulates mitophagy level to promote diabetic corneal epithelial wound healing

Cited by 32 publications

References 52 publications

Pathogenic Role of Endoplasmic Reticulum Stress in Diabetic Corneal Endothelial Dysfunction

Pathogenic Role of Endoplasmic Reticulum Stress in Diabetic Corneal Endothelial Dysfunction

PTEN Inhibition Facilitates Diabetic Corneal Epithelial Regeneration by Reactivating Akt Signaling Pathway

Sirtuins Modulation: A Promising Strategy for HIV-Associated Neurocognitive Impairments

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