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- Title
IDH2 Deficiency Promotes Endothelial Senescence by Eliciting miR-34b/c-Mediated Suppression of Mitophagy and Increased ROS Production.
- Authors
Lee, Ikjun; Piao, Shuyu; Kim, Seonhee; Nagar, Harsha; Choi, Su-jeong; Kim, Minsoo; Vu, Giang-Huong; Jeon, Byeong-Hwa; Kim, Cuk-Seong
- Abstract
Endothelial senescence impairs vascular function and thus is a primary event of age-related vasculature diseases. Isocitrate dehydrogenase 2 (IDH2) plays an important role in inducing alpha-ketoglutarate (α-KG) production and preserving mitochondrial function. However, the mechanism and regulation of IDH2 in endothelial senescence have not been elucidated. We demonstrated that downregulation of IDH2 induced accumulation of miR-34b/c, which impaired mitophagy and elevated mitochondrial reactive oxygen species (ROS) levels by inhibiting mitophagy-related markers (PTEN-induced putative kinase 1 (PINK1), Parkin, LC-II/LC3-I, and p62) and attenuating Sirtuin deacetylation 3 (Sirt3) expression. The mitochondrial dysfunction induced by IDH2 deficiency disrupted cell homeostasis and the cell cycle and led to endothelial senescence. However, miR-34b/c inhibition or α-KG supplementation restored Sirt3, PINK1, Parkin, LC-II/LC3-I, p62, and mitochondrial ROS levels, subsequently alleviating endothelial senescence. We showed that IDH2 played a crucial role in regulating endothelial senescence via induction of miR-34b/c in endothelial cells.
- Subjects
AGING; ISOCITRATE dehydrogenase; REACTIVE oxygen species; CELL cycle; ENDOTHELIAL cells
- Publication
Antioxidants, 2023, Vol 12, Issue 3, p585
- ISSN
2076-3921
- Publication type
Article
- DOI
10.3390/antiox12030585