Progressive dysfunction of the retinal pigment epithelium (RPE) and the adjacent photoreceptor cells in the outer retina plays a pivotal role in the pathogenesis of diabetic retinopathy (DR). Here, we observed a marked increase in oxidative stress-induced apoptosis in parallel with higher expression of telomeric protein TIN2 in RPE cells under hyperglycemia in vivo and in vitro. Delving deeper, we confirm that high glucose-induced elevation of mitochondria-localized TIN2 compromises mitochondrial activity and weakens the intrinsic antioxidant defense, thereby leading to the activation of mitochondria-dependent apoptotic pathways. Mechanistically, mitochondrial TIN2 promotes the phosphorylation of FOXO1 and its relocation to the mitochondria. Such translocation of transcription factor FOXO1 not only promotes its binding to the D-loop region of mitochondrial DNA—resulting in the inhibition of mitochondrial respiration—but also hampers its availability to nuclear target DNA, thereby undermining the intrinsic antioxidant defense. Moreover, TIN2 knockdown effectively mitigates oxidative-induced apoptosis in diabetic mouse RPE by preserving mitochondrial homeostasis, which concurrently prevents secondary photoreceptor damage. Our study proposes the potential of TIN2 as a promising molecular target for therapeutic interventions for diabetic retinopathy, which emphasizes the potential significance of telomeric proteins in the regulation of metabolism and mitochondrial function.

视网膜色素上皮 （RPE） 和视网膜外层邻近感光细胞的进行性功能障碍在糖尿病视网膜病变 （DR） 的发病机制中起着关键作用。在这里，我们观察到氧化应激诱导的细胞凋亡显着增加，同时在体内和体外高血糖下 RPE 细胞中端粒蛋白 TIN2 的表达升高。深入研究后，我们证实高葡萄糖诱导的线粒体定位 TIN2 升高会损害线粒体活性并削弱内在的抗氧化防御，从而导致线粒体依赖性凋亡途径的激活。从机制上讲，线粒体 TIN2 促进 FOXO1 的磷酸化及其重新定位到线粒体。转录因子 FOXO1 的这种易位不仅促进其与线粒体 DNA 的 D 环区域的结合，导致线粒体呼吸的抑制，而且还阻碍了其对核靶 DNA 的可用性，从而破坏了内在的抗氧化防御。此外，TIN2 敲除通过保持线粒体稳态有效减轻糖尿病小鼠 RPE 中氧化诱导的细胞凋亡，同时防止继发性光感受器损伤。我们的研究提出了 TIN2 作为糖尿病视网膜病变治疗干预的有前途的分子靶点的潜力，这强调了端粒蛋白在代谢和线粒体功能调节中的潜在意义。