SIRT3 mitigates high glucose-induced damage in retinal microvascular endothelial cells via OPA1-mediated mitochondrial dynamics.

Exp Cell Res

Department of Ophthalmology and Vision Science, Eye and ENT Hospital, Fudan University, Shanghai, China; Key Laboratory of Myopia of State Health Ministry, and Key Laboratory of Visual Impairment and Restoration of Shanghai, Shanghai, China. Electronic address:

Published: November 2024

AI Article Synopsis

  • Oxidative stress in endothelial cells contributes significantly to diabetic retinopathy (DR), and maintaining mitochondrial homeostasis is crucial for reducing this stress.
  • The study investigated how mitochondrial sirtuins (SIRTs), specifically SIRT3, affect oxidative stress and mitochondrial function in retinal microvascular endothelial cells exposed to high glucose (HG) conditions.
  • Findings revealed that high glucose exposure decreased cell viability and SIRT3 levels while increasing cell death and reactive oxygen species (ROS), but overexpressing SIRT3 helped restore cell health and mitochondrial dynamics, particularly via the optic atrophy 1 (OPA1) pathway.

Article Abstract

Oxidative stress in endothelial cells is pivotal in diabetic retinopathy (DR), with mitochondrial homeostasis being crucial to mitigate this stress. This study explored the roles of mitochondrial sirtuins (SIRTs) in high glucose (HG)-induced oxidative stress, related endothelial impairment, and mitochondrial homeostasis damage in rat retinal microvascular endothelial cells (RMECs). RMECs were cultured under HG or equivalent osmotic conditions. Cell viability was assessed using the Cell Counting Kit-8 assay, whereas cell death and survival were determined via calcein-AM/propidium iodide double staining. Reactive oxygen species (ROS) levels were measured using 2',7'-dichlorofluorescein fluorescence. Expression of mitochondrial SIRTs3-5 and key mitochondrial homeostasis molecules was quantified by the quantitative real-time polymerase chain reaction and confirmed by western blotting. Mitochondrial morphology was evaluated using electron microscopy and the MitoTracker fluorescent probe. A SIRT3-overexpressing RMEC line was constructed to assess the role of SIRT3 in oxidative stress and mitochondrial dynamics. After 48 h of HG exposure, cell viability was significantly reduced, with a concomitant increase in cell death and ROS levels, alongside a marked decrease in SIRT3 expression and molecules associated with mitochondrial dynamics. SIRT3 overexpression reversed these effects, particularly increasing the mitochondrial fusion-related molecule, optic atrophy 1 (OPA1). However, the OPA1 inhibitor, MYLS22, blocked the protective effect of SIRT3, leading to more dead cells, a higher ROS level, and intensified mitochondrial fragmentation. These results suggest that SIRT3 is involved in HG-induced imbalanced mitochondrial dynamics of endothelial cells in DR, potentially through the OPA1 pathway.

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http://dx.doi.org/10.1016/j.yexcr.2024.114320DOI Listing

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