bims-mideyd 2022-03-06 papers

Sci Adv. 2022 Mar 04. 8(9): eabn2070

Mitochondria in cone photoreceptors act as microlenses to enhance photon delivery and confer directional sensitivity to light.

John M Ball, Shan Chen, Wei Li.

Mammalian photoreceptors aggregate numerous mitochondria, organelles chiefly for energy production, in the ellipsoid region immediately adjacent to the light-sensitive outer segment to support the high metabolic demands of phototransduction. However, these complex, lipid-rich organelles are also poised to affect light passage into the outer segment. Here, we show, via live imaging and simulations, that despite this risk of light scattering or absorption, these tightly packed mitochondria "focus" light for entry into the outer segment and that mitochondrial remodeling affects such light concentration. This "microlens"-like feature of cone mitochondria delivers light with an angular dependence akin to the Stiles-Crawford effect (SCE), providing a simple explanation for this essential visual phenomenon that improves resolution. This new insight into the optical role of mitochondria is relevant for the interpretation of clinical ophthalmological imaging, lending support for the use of SCE as an early diagnostic tool in retinal disease.

DOI: https://doi.org/10.1126/sciadv.abn2070

Exp Eye Res. 2022 Feb 28. pii: S0014-4835(22)00096-3. [Epub ahead of print] 109015

Effect of Sirt3 on retinal pigment epithelial cells in high glucose through Foxo3a/ PINK1-Parkin pathway mediated mitophagy.

Li Huang, Tianyu Yao, Jie Chen, Zhiru Zhang, Wei Yang, Xiaorong Gao, Yujiao Dan, Yue He.

Sirt3 is closely associated with mitophagy. This study aimed to investigate the effect and potential mechanism of Sirt3 on mitophagy in retinal pigment epithelium (RPE) in a high glucose environment. The expression levels of Sirt3, Foxo3a, PINK1, Parkin and LC3B in RPE subjected to high-glucose (HG, 30 mM D-glucose) conditions were detected by RT-PCR and western blotting. Dichloro-dihydro-fluorescein diacetate (DCFH-DA) staining was used to detect the level of reactive oxygen species (ROS) in RPE treated with HG. MitoTracker and LysoTracker probes were used to label mitochondria and lysosomes, respectively, to observe the occurrence of autophagy. Sirt3-dependent regulation of mitophagy through the Foxo3a/PINK1-Parkin pathway was further investigated by virus transfection-mediated Sirt3 overexpression and PINK1 silencing. The effect of Sirt3 overexpression on apoptosis was detected by flow cytometry. The Sirt3 expression was decreased, the Foxo3a/PINK1-Parkin pathway was inhibited, intracellular ROS level was increased, and mitophagy was attenuated in RPE under HG condition. Sirt3 overexpression activated the Foxo3a/PINK1-Parkin signaling pathway and mitophagy, and inhibited cell apoptosis. Silencing PINK1 inhibited the effect of Sirt3 overexpression on mitophagy. In summary, Sirt3 can activate mitophagy through the Foxo3a/PINK1-Parkin pathway and reduce HG-induced apoptosis of RPE. This study provides a new direction to understand the pathogenesis and develop a potential therapeutic target for diabetic retinopathy.

Keywords: Diabetic retinopathy; Foxo3a; Mitophagy; PINK1; Parkin; Sirt3

DOI: https://doi.org/10.1016/j.exer.2022.109015

Invest Ophthalmol Vis Sci. 2022 Mar 02. 63(3): 4

Pathogenic Role of Endoplasmic Reticulum Stress in Diabetic Corneal Endothelial Dysfunction.

Chen Chen, Bin Zhang, Junfa Xue, Zongyi Li, Shengqian Dou, Huilin Chen, Qun Wang, Mingli Qu, Huifeng Wang, Yuan Zhang, Luqin Wan, Qingjun Zhou, Lixin Xie.

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.

DOI: https://doi.org/10.1167/iovs.63.3.4