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TIN2 modulates FOXO1 mitochondrial shuttling to enhance oxidative stress-induced apoptosis in retinal pigment epithelium under hyperglycemia

Cell Death & Differentiation (2024)Cite this article

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Abstract

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.

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Fig. 1: Oxidative stress-induced apoptosis is increased accompanied by elevated TIN2 expression in RPE under hyperglycemia in vivo and in vitro.
Fig. 2: Increased TIN2 expression in RPE under high glucose induces apoptosis by activating mitochondrial-dependent pathways.
Fig. 3: Increased mitochondria-localized TIN2 but not nuclear TIN2 contributed to high glucose induced-deleterious effects on cellular homeostasis.
Fig. 4: Increased mitochondria-localized TIN2 under high glucose modulates essential mitochondria function and hampers endogenous antioxidative capacity.
Fig. 5: Increased mitochondria-localized TIN2 under high glucose inhibits mitochondrial respiration by recruiting FOXO1 to the D-loop region of mtDNA.
Fig. 6: Enhanced FOXO1 mitochondria shuttling due to elevated mitochondrial TIN2 aggravates RPE apoptosis with weakened antioxidative defense.
Fig. 7: TIN2 knockdown attenuates oxidative-induced apoptosis in diabetic mRPE and secondary photoreceptor loss via preservation of mRPE mitochondrial homeostasis.

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The data analyzed in this study are included in this article and the supplementary data files. Additional data will be made available on request.

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Acknowledgements

We thank all the members in Shanghai Key Laboratory of Ocular Fundus Diseases for their expertise and technical assistance.

Funding

The work was supported by the National Science Foundation of China (Grant No.81970812), the National Key R&D Program of China (Grant No. 2016YFC0904800, 2019YFC0840607), the National Science and Technology Major Project of China (Grant No. 2017ZX09304010).

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  1. These authors contributed equally: Shimei Chen, Dandan Sun.

Authors and Affiliations

  1. Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China

    Shimei Chen, Dandan Sun, Shuchang Zhang, Li Xu, Ning Wang, Xun Xu & Fang Wei

  2. National Clinical Research Center for Eye Diseases; Shanghai Key Laboratory of Ocular Fundus Disease; Shanghai Engineering Center for Visual Science and Photo Medicine; Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai, 200080, China

    Shimei Chen, Dandan Sun, Shuchang Zhang, Li Xu, Ning Wang, Xun Xu & Fang Wei

  3. Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Huiming Li

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Contributions

Research design and conceptualization: SC, DS, HL and FW. Methodology: SC, SZ, LX and NW. Data analysis: SC, SZ, DS and XX. Figure creation: SC, FW, XX and HL. Writing—original draft: SC and DS. Writing—review & editing: SC, DS, FW, HL and XX.

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Correspondence to Huiming Li, Xun Xu or Fang Wei.

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All in vivo animal tests were conducted in strict accordance with the Association for Research in Vision and Ophthalmology (ARVO) standards regarding the use of animals in vision and ophthalmology research. Animal research was approved by the Ethics Committee of Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (reference number: 2020-A068-02).

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Chen, S., Sun, D., Zhang, S. et al. TIN2 modulates FOXO1 mitochondrial shuttling to enhance oxidative stress-induced apoptosis in retinal pigment epithelium under hyperglycemia. Cell Death Differ (2024). https://doi.org/10.1038/s41418-024-01349-8

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