The m6A reader YTHDC2 promotes SIRT3 expression by reducing the stabilization of KDM5B to improve mitochondrial metabolic reprogramming in diabetic peripheral neuropathy.

Yang Jiao, Shu Wang, Xin Wang, Ling Yin, Yue-Hua Zhang, Yi-Ze Li, Yong-Hao Yu

Acta diabetologica 2023 Mar

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Diabetic peripheral neuropathy (DPN) is a common diabetic complication. Aberrant mitochondrial function causes neurodegeneration under hyperglycemia-induced metabolic stress, which in turn results in DPN progression. m6A and m6A reader (YTHDC2) are closely related to diabetes and diabetes complications, while the role of YTHDC2 in regulating mitochondrial metabolism in DPN needs to be further probed. For HG treatment, Schwann cells (RSC96) were subjected to D-glucose for 72 h. db/db mice were used as the diabetic mouse model. Me-RIP assay was performed to evaluate KDM5B m6A level. RNA degradation assay was conducted to examine KDM5B mRNA stability. In addition, OCR and ECAR were examined by XF96 Analyzer. Moreover, the content of ATP and PDH activity in RSC96 cells were detected using kits, and the level of ROS was detected using MitoSOX staining. RIP, RNA pull-down and dual-luciferase reporter gene assays were carried out to verify the binding relationships between YTHDC2, KDM5B and SIRT3. We first observed that KDM5B expression and KDM5B mRNA stabilization were significantly increased in DPN. The m6A reader YTHDC2 was lowly expressed in DPN. Meanwhile, YTHDC2 over expression decreased KDM5B mRNA stability in an m6A-dependent manner. Our results also revealed that YTHDC2 overexpression resulted in reduced ROS level and increased ATP level, PDH activity, OCR and ECAR in HG-treated Schwann cells, while these effects were reversed by KDM5B overexpression. Additionally, SIRT3 served as the target of YTHDC2/KDM5B axis in regulating mitochondrial metabolism in DPN. Taken together, YTHDC2 promoted SIRT3 expression by reducing the stabilization of KDM5B to improve mitochondrial metabolic reprogramming in DPN. © 2022. Springer-Verlag Italia S.r.l., part of Springer Nature.

Citation

Yang Jiao, Shu Wang, Xin Wang, Ling Yin, Yue-Hua Zhang, Yi-Ze Li, Yong-Hao Yu. The m6A reader YTHDC2 promotes SIRT3 expression by reducing the stabilization of KDM5B to improve mitochondrial metabolic reprogramming in diabetic peripheral neuropathy. Acta diabetologica. 2023 Mar;60(3):387-399