TIN2 modulates FOXO1 mitochondrial shuttling to enhance oxidative stress-induced apoptosis in retinal pigment epithelium under hyperglycemia.
Shimei ChenDandan SunShuchang ZhangLi XuNing WangHuiming LiXun XuFang WeiPublished in: Cell death and differentiation (2024)
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. Created with BioRender ( https://www.biorender.com/ ).
Keyphrases
- induced apoptosis
- oxidative stress
- diabetic retinopathy
- diabetic rats
- transcription factor
- high glucose
- mitochondrial dna
- signaling pathway
- ischemia reperfusion injury
- dna damage
- cell death
- optical coherence tomography
- oxide nanoparticles
- perovskite solar cells
- endothelial cells
- endoplasmic reticulum stress
- multiple sclerosis
- copy number
- dna binding
- type diabetes
- risk assessment
- physical activity
- single molecule
- pi k akt
- drug induced
- cell cycle arrest